Methods and agents for treating disease

ABSTRACT

The present invention provides compounds having the general structural formula (I) [formula should be inserted here] and pharmaceutically acceptable derivatives thereof, as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of conditions or diseases involving elevated levels of aldosterone or abnormal or excessive fibrosis, such as kidney disease and hypertension.

GOVERNMENT SUPPORT

This invention was made with government support under DK095625 awardedby the National Institutes of Health. The government has certain rightsin the invention.

BACKGROUND OF THE INVENTION

The renin-angiotensin-aldosterone system (RAAS) plays a critical role inrenal physiology. Inhibitors of angiotensin-converting enzyme (ACE) orangiotensin receptor blockers (ARB) are the mainstay in the clinicalmanagement of hypertension and renal disorders such as CKD. Thesetreatments are thought to work in large part by reducing aldosteronelevels. Despite initial success of ACE inhibition or ARB therapy toreduce aldosterone, in 30-40% of patients, aldosterone is eventuallyfound to return to pretreatment levels, thus severely limiting the longterm therapeutic effectiveness. The clinical significance of this“aldosterone breakthrough” is increasingly recognized and severalapproaches to combat aldosterone escape are being considered. Themineralocorticoid aldosterone has long been known as a key hormone thatregulates electrolyte homeostasis, fluid volume and blood pressure.Aldosterone acts through the mineralocorticoid receptor (MR) in thedistal nephrons of the kidney to control sodium re-absorption andpotassium excretion. In patients with chronic renal disease, plasmaaldosterone levels are usually found to be elevated and to correlatewith proteinuria. Aldosterone is thought to directly accelerate renaldamage by sustaining cell growth, inflammation and fibrosis.

One in ten American adults have some level of chronic kidney disease(CKD), which amounts to more than 20 million US citizens. CKD occurs inboth diabetic and non-diabetic nephropathies and is characterized byincreasing proteinuria, declining functional nephron mass and aconcomitant decline in renal function (glomerular filtration rate(GRF)<60 ml/min). It is estimated that 20-40% of diabetes patientsprogress to some form of CKD. In 2004, approximately 8 million people inthe US were diagnosed with a glomerular filtration rate <60 ml/min. CKDoften transitions to end-stage renal disease, a life-threateningcondition requiring renal replacement therapy. The number of patientsreaching end-stage renal disease has been increasing at an average of 7%per year over the last 10 years. Worldwide, approximately 1.1 millionpatients are on renal replacement therapy and this number is expected toexceed 2 million in 10 years, with 0.5 million from the US. Many peoplewill die as a result of renal failure if renal replacement therapy isnot provided. The annual mortality rate is 20% for patients on dialysiswho are waiting for renal transplantation. The combined cost of dialysisand kidney transplantation is estimated to exceed $1 trillion. Atpresent, there is no treatment reverses the course of CKD. Many patientswith kidney disease benefit from antihypertensive therapy withinhibitors of angiotensin converting enzyme (ACE) or angiotensinreceptor blockers (ARBs). These drugs are usually given in concert withdiuretics. However, despite initial success of ACE inhibition or ARBtherapy, their long term therapeutic effectiveness is often limited.There continues to be a great unmet medical need for therapies that cancomplement the current pharmaceutical armamentarium by slowing diseaseprogression, reversing symptoms and delaying or preventing the need forrenal replacement therapy. There is also a need for compounds that canprevent the development of fibrosis.

SUMMARY OF THE INVENTION

In one embodiment, certain novel inventive compounds have the structureshown in Formula (I) below:

-   -   or a salt, solvate, enantiomer, ester, or hydrate thereof;    -   wherein R¹ and R² are each independently one or more H, halogen,        haloalkyl, NO₂, CN, COOR⁵, SO₂R⁵, CONR⁵R⁶, SO₂NR⁵R⁶, NR⁵R⁶, OR⁵,        alkyl, alkenyl, alkynyl, heteroalkyl, aryl or hetero aryl, any        of which is further substituted by one or more R⁷; or two R²        substituents taken together with the respective carbon atom to        which they are attached, form a 5-6 membered heterocyclic ring,        wherein said ring is optionally substituted with one or more R⁷;    -   R³ is H, alkyl, alkenyl or alkynyl, any of which is further        substituted by one or more R⁷;    -   R⁴ is H, NR⁵R⁶, SR⁵, or OR⁵;    -   R⁵ and R⁶ are independently hydrogen, alkyl, aryl, heteroaryl or        haloalkyl;    -   R⁷ is H, halogen, alkyl, haloalkyl, NO₂, CN, COOR⁸, SO₂R⁸,        CONR⁸R⁹, SO₂NR⁸R⁹, NR⁸R⁹, or OR⁸; and    -   R⁸ and R⁹ are independently hydrogen, alkyl or haloalkyl.

In certain embodiments, R¹ is methoxy, ethyloxy, 1-propyloxy or2-propyloxy. In certain embodiments, R² is trifluoromethoxy ormethylenedioxy optionally further substituted with difluoro.

In another embodiment, a pharmaceutical composition is providedcomprising a compound of Formula I and a diluent, excipient, carrier, orone or more other components to facilitate the administration of acompound embodied here to a subject in need thereof.

In one embodiment, compounds of the invention inhibit aldosteronesynthase. In one embodiment, compounds of the invention inhibit CYP11B2.In another embodiment, compounds of the invention selectively inhibitCYP11B2 compared to CYP11B1.

In another aspect, the present invention is directed to a method ofprevention, treatment or lessening of the severity of a condition ordisease associated with or characterized by increased or elevatedaldosterone levels, comprising administering to a subject in needthereof an effective amount of a compound of Formula I or apharmaceutical composition thereof.

In another aspect, the present invention is directed to a method ofprevention, treatment or lessening of the severity of a condition ordisease associated with or characterized by increased fibrosis,comprising administering to a subject in need thereof an effectiveamount of a compound of Formula I or a pharmaceutical compositionthereof.

In certain embodiments, the diseases and conditions benefited bytreatment with an effective amount of a compound mentioned above orpharmaceutical composition thereof include but are not limited tochronic renal disease and hypertension. Other conditions related toelevated aldosterone levels, or hyperaldosteronism, include hypertensivevascular complications (hypertrophy followed by sclerosis of intimalsmooth muscle), renal complications (sclerosis), and cardiaccomplications (hypertrophy followed by dilatation). Symptoms of elevatedaldosterone levels treatable by the compounds, compositions and methodsherein include fatigue, headache, hypokalemia, hypernatraemia,hypomagnesemia, intermittent or temporary paralysis, muscle spasms,muscle weakness, numbness, polyuria, polydipsia, tingling, and metabolicalkalosis, by way of non-limiting examples.

In certain embodiments, the diseases and conditions benefited bytreatment with an effective amount of a compound mentioned above orpharmaceutical composition thereof include but are not limited tofibrotic liver disease, hepatic ischemia-reperfusion injury, cerebralinfarction, ischemic heart disease, cardiac fibrosis, renal disease orlung (pulmonary) fibrosis. In other embodiments, the disease orcondition is liver fibrosis associated with hepatitis C, hepatitis B,delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis,extrahepatic obstructions (stones in the bile duct), cholangiopathies(primary biliary cirrhosis and sclerosing cholangitis), autoimmune liverdisease, and inherited metabolic disorders (Wilson's disease,hemochromatosis, and alpha-1 antitrypsin deficiency); damaged and/orischemic organs, transplants or grafts; ischemia/reperfusion injury;stroke; cerebrovascular disease; myocardial ischemia; atherosclerosis;pancreatitis; renal failure; renal fibrosis; chronic kidney disease;polycystic kidney disease; scleroderma; systemic sclerosis; dermalfibrosis and idiopathic pulmonary fibrosis. In still furtherembodiments, the treatment is for wounds for acceleration of healing;reducing post-surgical scarring; reducing adhesion formation;vascularization of a damaged and/or ischemic organ, transplant or graft;amelioration of ischemia/reperfusion injury in the brain, heart, liver,kidney, and other tissues and organs; normalization of myocardialperfusion as a consequence of chronic cardiac ischemia or myocardialinfarction; development or augmentation of collateral vessel developmentafter vascular occlusion or to ischemic tissues or organs; fibroticdiseases; hepatic disease including fibrosis and cirrhosis; lungfibrosis; radiocontrast nephropathy; fibrosis secondary to renalobstruction; renal trauma and transplantation; renal failure secondaryto chronic diabetes and/or hypertension; muscular dystrophy, amyotrophiclateral sclerosis, and/or diabetes mellitus.

Definitions

It is understood that the compounds, as described herein, may besubstituted with any number of substituents or functional moieties. Ingeneral, the term “substituted” whether preceded by the term“optionally” or not, and substituents contained in formulas of thisinvention, refer to the replacement of hydrogen radicals in a givenstructure with the radical of a specified substituent. When more thanone position in any given structure may be substituted with more thanone substituent selected from a specified group, the substituent may beeither the same or different at every position. As used herein, the term“substituted” is contemplated to include all permissible substituents oforganic compounds. In a broad aspect, the permissible substituentsinclude acyclic and cyclic, branched and unbanked, carbocyclic andheterocyclic, aromatic and non-aromatic, carbon and heteroatomsubstituents of organic compounds. For purposes of this invention,heteroatoms such as nitrogen may have hydrogen substituents and/or anypermissible substituents of organic compounds described herein whichsatisfy the valencies of the heteroatoms. Furthermore, this invention isnot intended to be limited in any manner by the permissible substituentsof organic compounds. Combinations of substituents and variablesenvisioned by this invention are preferably those that result in theformation of stable compounds useful in the treatment and prevention,for example of disorders, as described generally above. Examples ofsubstituents include, but are not limited to aliphatic; heteroaliphatic;alicyclic; heterocyclic; aromatic, heteroaromatic; aryl; heteroaryl;alkylaryl; aralkyl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy;heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F;Cl; Br; I; —NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂;—CH₂SO₂CH₃; or -GR^(G1) wherein G is —O—, —S—, —NR^(G2)—, —C(═O)—,—S(═O)—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)—, —NR^(G2)C(═O)—,—OC(═O)O—, —OC(═O)NR^(G2-), —NR^(G2)C(═O)O—, —NR^(G2)C(═O)NR^(G2)—,—C(═S)—, —C(═S)S—, —SC(═S)—, —SC(═S)S—, —C(═NR^(G2))—, —C(═NR^(G2))O—,—C(═NR^(G2))NR^(G3)—, —OC(═NR^(G2))—, —NR^(G2)C(═NR^(G3))—,—NR^(G2)SO₂—, —NR^(G2) SO₂NR^(G3)—, or —SO₂NR^(G2)—, wherein eachoccurrence of R^(G1), R^(G2) and R^(G3) independently includes, but isnot limited to, hydrogen, halogen, or an optionally substitutedaliphatic, heteroaliphatic, alicyclic, heterocyclic, aromatic,heteroaromatic, aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety.Additional examples of generally applicable substituents are illustratedby the specific embodiments shown in the Examples that are describedherein.

The term “stable”, as used herein, preferably refers to compounds whichpossess stability sufficient to allow manufacture and which maintain theintegrity of the compound for a sufficient period of time to be detectedand preferably for a sufficient period of time to be useful for thepurposes detailed herein.

The term “aliphatic”, as used herein, includes both saturated andunsaturated, straight chain (i.e., unbranched) or branched aliphatichydrocarbons as defined by IUPAC, which are optionally substituted withone or more functional groups. As defined herein, “aliphatic” isintended to include optionally substituted alkyl, alkenyl and alkynylmoieties. Thus, as used herein, the term “alkyl” includes straight andbranched alkyl groups. An analogous convention applies to other genericterms such as “alkenyl”, “alkynyl” and the like. Furthermore, as usedherein, the terms “alkyl”, “alkenyl”, “alkynyl” and the like encompassboth substituted and unsubstituted groups. In certain embodiments, asused herein, “lower alkyl” is used to indicate those alkyl groups(substituted, unsubstituted, branched or unbranched) having about 1-6carbon atoms. In some instances aliphatic can include alicyclic orcycloalkyl, including unsaturations therein.

In certain embodiments, the alkyl, alkenyl and alkynyl groups employedin the invention contain 1-20; 2-20; 3-20; 4-20; 5-20; 6-20; 7-20 or8-20 aliphatic carbon atoms. In certain other embodiments, the alkyl,alkenyl, and alkynyl groups employed in the invention contain 1-10;2-10; 3-10; 4-10; 5-10; 6-10; 7-10 or 8-10 aliphatic carbon atoms. Inyet other embodiments, the alkyl, alkenyl, and alkynyl groups employedin the invention contain 1-8; 2-8; 3-8; 4-8; 5-8; 6-20 or 7-8 aliphaticcarbon atoms. In still other embodiments, the alkyl, alkenyl, andalkynyl groups employed in the invention contain 1-6; 2-6; 3-6; 4-6 or5-6 aliphatic carbon atoms. In yet other embodiments, the alkyl,alkenyl, and alkynyl groups employed in the invention contain 1-4; 2-4or 3-4 carbon atoms. Illustrative aliphatic groups thus include, but arenot limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl,n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl,isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, whichagain, may bear one or more substituents. Alkenyl groups include, butare not limited to, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, and the like. Representative alkynyl groupsinclude, but are not limited to, ethynyl, 2-propynyl (propargyl),1-propynyl and the like.

The term “alicyclic”, as used herein, refers to compounds that combinethe properties of aliphatic and cyclic compounds and include but are notlimited to cyclic, or polycyclic aliphatic hydrocarbons and bridgedcycloalkyl compounds, which are optionally substituted with one or morefunctional groups. As will be appreciated by one of ordinary skill inthe art, “alicyclic” is intended herein to include, but is not limitedto, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which areoptionally substituted with one or more functional groups. Illustrativealicyclic groups thus include, but are not limited to, for example,cyclopropyl, —CH₂-cyclopropyl, cyclobutyl, —CH₂-cyclobutyl, cyclopentyl,—CH₂-cyclopentyl, cyclohexyl, —CH₂-cyclohexyl, cyclohexenylethyl,cyclohexanylethyl, norbornyl moieties and the like, which again, maybear one or more substituents.

The term “cycloalkyl”, as used herein, refers to cyclic alkyl groups,specifically to groups having three to seven, preferably three to tencarbon atoms. Suitable cycloalkyls include, but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and thelike, which, as in the case of aliphatic, heteroaliphatic orheterocyclic moieties, may optionally be substituted. An analogousconvention applies to other generic terms such as “cycloalkenyl”,“cycloalkynyl” and the like. Additional examples of generally applicablesubstituents are illustrated by the specific embodiments shown in theExamples that are described herein.

The term “heteroaliphatic”, as used herein, refers to aliphatic moietiesin which one or more carbon atoms in the main chain have been replacedwith a heteroatom. Thus, a heteroaliphatic group refers to an aliphaticchain which contains one or more oxygen, sulfur, nitrogen, phosphorus orsilicon atoms in place of carbon atoms in the aliphatic main chain.Heteroaliphatic moieties may be branched or linear unbranched. Incertain embodiments, heteroaliphatic moieties are substituted byindependent replacement of one or more of the hydrogen atoms thereonwith one or more moieties including, but not limited to aliphatic;heteroaliphatic; alicyclic; heterocyclic; aromatic, heteroaromatic;aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy; aryloxy;heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio;heteroarylthio; F; Cl; Br; I; —NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH;—CH₂CH₂OH; —CH₂NH₂; —CH₂SO₂CH₃; or -GR^(G1) wherein G is —O—, —S—,—NR^(G2-), —C(═O)—, —S(═O)—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)—,—NR^(G2)C(═O)—, —OC(═O)O—, —OC(═O)NR^(G2)—, —NR^(G2)C(═O)O—,—NR^(G2)C(═O)NR^(G2)—, —C(═S)—, —C(═S)S—, —SC(═S)—, —SC(═S)S—,—C(═NR^(G2))—, —C(═NR^(G2))O—, —C(═NR^(G2))NR^(G3)—, —OC(═NR^(G2))—,—NR^(G2)C(═NR^(G3))—, —NR^(G2)SO₂—, —NR^(G2)SO₂NR^(G3)— or —SO₂NR^(G2)—,wherein each occurrence of R^(G1), R^(G2) and R^(G3) independentlyincludes, but is not limited to, hydrogen, halogen, or an optionallysubstituted aliphatic, heteroaliphatic, alicyclic, heterocyclic,aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, oralkylheteroaryl moiety. Additional examples of generally applicablesubstituents are illustrated by the specific embodiments shown in theExamples that are described herein.

The term “heteroalicyclic”, “heterocycloalkyl” or “heterocyclic”, asused herein, refers to compounds which combine the properties ofheteroaliphatic and cyclic compounds and include but are not limited tosaturated and unsaturated mono- or polycyclic ring systems having 5-16atoms wherein at least one ring atom is a heteroatom selected from O, Sand N (wherein the nitrogen and sulfur heteroatoms may be optionally beoxidized), wherein the ring systems are optionally substituted with oneor more functional groups, as defined herein. In certain embodiments,the term “heterocyclic” refers to a non-aromatic 5-, 6- or 7-memberedring or a polycyclic group, including, but not limited to a bi- ortri-cyclic group comprising fused six-membered rings having between oneand three heteroatoms independently selected from oxygen, sulfur andnitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds andeach 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen andsulfur heteroatoms may optionally be oxidized, (iii) the nitrogenheteroatom may optionally be quaternized, and (iv) any of the aboveheterocyclic rings may be fused to an aryl or heteroaryl ring.Representative heterocycles include, but are not limited to,pyrrolidinyl, pyrazolinyl, pyrazolidinyl imidazolinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. In certainembodiments, a “substituted heterocycloalkyl or heterocycle” group isutilized and as used herein, refers to a heterocycloalkyl or heterocyclegroup, as defined above, substituted by the independent replacement ofone or more hydrogen atoms thereon with aliphatic; heteroaliphatic;alicyclic; heterocyclic; aromatic, heteroaromatic; aryl; heteroaryl;alkylaryl; alkylheteroaryl; alkoxy; aryloxy; heteroalkoxy;heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F;Cl; Br; I; —NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂;—CH₂SO₂CH₃; or -GR^(G1) wherein G is —O—, —S—, —NR^(G2)—, —C(═O)—,—S(═O)—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)—, —NR^(G2)C(═O)—,—OC(═O)O—, —OC(═O)NR^(G2)—, —NR^(G2)C(═O)O—, —NR^(G2)C(═O)NR^(G2)—,—C(═S)—, —C(═S)S—, —SC(═S)—, —SC(═S)S—, —C(═NR^(G2))—, —C(═NR^(G2))O—,—C(═NR^(G2))NR^(G3)—, —OC(═NR^(G2))—, —NR^(G2)C(═NR^(G3)), —NR^(G2)SO₂—,—NR^(G2)SO₂NR^(G3)—, or —SO₂NR^(G2)—, wherein each occurrence of R^(G1),R^(G2) and R^(G3) independently includes, but is not limited to,hydrogen, halogen, or an optionally substituted aliphatic,heteroaliphatic, alicyclic, heterocyclic, aromatic, heteroaromatic,aryl, heteroaryl, alkylaryl, or alkylheteroaryl moiety. Additionalexamples or generally applicable substituents are illustrated by thespecific embodiments shown in the Examples, which are described herein.

Additionally, it will be appreciated that any of the alicyclic orheterocyclic moieties described above and herein may comprise an aryl orheteroaryl moiety fused thereto. Additional examples of generallyapplicable substituents are illustrated by the specific embodimentsshown in the Examples that are described herein.

In general, the term “aromatic moiety”, as used herein, refers to astable mono- or polycyclic, unsaturated moiety having preferably 3-14carbon atoms, each of which may be substituted or unsubstituted. Incertain embodiments, the term “aromatic moiety” refers to a planar ringhaving p-orbitals perpendicular to the plane of the ring at each ringatom and satisfying the Huckel rule where the number of pi electrons inthe ring is (4n+2) wherein n is an integer. A mono- or polycyclic,unsaturated moiety that does not satisfy one or all of these criteriafor aromaticity is defined herein as “non-aromatic”, and is encompassedby the term “alicyclic”. Examples of aromatic moieties include, but arenot limited to, phenyl, indanyl, indenyl, naphthyl, phenanthryl andanthracyl.

In general, the term “heteroaromatic moiety”, as used herein, refers tostable substituted or unsubstituted unsaturated mono-heterocyclic orpolyheterocyclic moieties having preferably 3-14 carbon atoms,comprising at least one ring having p-orbitals perpendicular to theplane of the ring at each ring atom, and satisfying the Huckel rulewhere the number of pi electrons in the ring is (4n+2) wherein n is aninteger. Examples of heteroaromatic moieties include, but are notlimited to, pyridyl, quinolinyl, dihydroquinolinyl, isoquinolinyl,quinazolinyl, dihydroquinazolyl, and tetrahydroquinazolyl.

It will also be appreciated that aromatic and heteroaromatic moieties,as defined herein, may be attached via an aliphatic (e.g., alkyl) orheteroaliphatic (e.g., heteroalkyl) moiety and thus also includemoieties such as -(aliphatic)aromatic, -(heteroaliphatic)aromatic,-(aliphatic)heteroaromatic, -(heteroaliphatic)heteroaromatic,-(alkyl)aromatic, -(heteroalkyl)aromatic, -(alkyl)heteroaromatic, and-(heteroalkyl)heteroaromatic moieties. Thus, as used herein, the phrases“aromatic or heteroaromatic moieties” and “aromatic, heteroaromatic,-(alkyl)aromatic, -(heteroalkyl)aromatic, -(heteroalkyl)heteroaromatic,and -(heteroalkyl)heteroaromatic” are interchangeable. In some instancescorresponding moieties may be referred to synonymously as aralkyl,heteroaralkyl and the like. Substituents include, but are not limitedto, any of the previously mentioned substituents, i.e., the substituentsrecited for aliphatic moieties, or for other moieties as disclosedherein, resulting in the formation of a stable compound.

In general, the term “aryl” refers to aromatic moieties, as describedabove, excluding those attached via an aliphatic (e.g., alkyl) orheteroaliphatic (e.g., heteroalkyl) moiety. In certain embodiments ofthe present invention, “aryl” refers to a mono- or bicyclic carbocyclicring system having one or two rings satisfying the Huckel rule foraromaticity, including, but not limited to, phenyl, naphthyl,tetrahydronaphthyl, indanyl, indenyl and the like.

Similarly, the term “heteroaryl” refers to heteroaromatic moieties, asdescribed above, excluding those attached via an aliphatic (e.g., alkyl)or heteroaliphatic (e.g., heteroalkyl) moiety. In certain embodiments ofthe present invention, the term “heteroaryl”, as used herein, refers toa cyclic unsaturated radical having from about five to about ten ringatoms of which one ring atom is selected from S, O and N; zero, one ortwo ring atoms are additional heteroatoms independently selected from S,O and N; and the remaining ring atoms are carbon, the radical beingjoined to the rest of the molecule via any of the ring atoms, such as,for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the like.

As defined herein, “aryl” and “heteroaryl” groups (including bicyclicaryl groups) can be unsubstituted or substituted, wherein substitutionincludes replacement of one or more of the hydrogen atoms thereonindependently with any of the previously mentioned substitutents, i.e.,the substituents recited for aliphatic moieties, or for other moietiesas disclosed herein, resulting in the formation of a stable compound.For example, aryl and heteroaryl groups (including bicyclic aryl groups)can be unsubstituted or substituted, wherein substitution includesreplacement of one or more of the hydrogen atoms thereon independentlywith any one or more of the following moieties including, but notlimited to: aliphatic; heteroaliphatic; alicyclic; heterocyclic;aromatic, heteroaromatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl;alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;heteroalkylthio; heteroarylthio; F; Cl; Br; I; —NO₂; —CN; —CF₃; —CH₂CF₃;—CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂; —CH₂SO₂CH₃; or -GR^(G1) wherein G is—O—, —S—, —NR^(G2)—, —C(═O)—, —S(═O)—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2)—,—OC(═O)—, —NR^(G2)C(═O)—, —OC(═O)O—, —OC(═O)NR^(G2)—, —NR^(G2)C(═O)O—,—NR^(G2)C(═O)NR^(G2)—, —C(═S)—, —C(═S)S—, —SC(═S)—, —SC(═S)S—,—C(═NR^(G2))—, —C(═NR^(G2))O—, —C(═NR^(G2))NR^(G3)—, —OC(═NR^(G2))—,—NR^(G2)C(═NR^(G3))—, —NR^(G2)SO₂—, —NR^(G2)SO₂NR^(G3)—, or—SO₂NR^(G2)—, wherein each occurrence of R^(G1), R^(G2) and R^(G3)independently includes, but is not limited to, hydrogen, halogen, or anoptionally substituted aliphatic, heteroaliphatic, alicyclic,heterocyclic, aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, oralkylheteroaryl moiety. Additionally, it will be appreciated, that anytwo adjacent groups taken together may represent a 4, 5, 6, or7-membered substituted or unsubstituted alicyclic or heterocyclicmoiety. Additional examples of generally applicable substituents areillustrated by the specific embodiments shown in the Examples that aredescribed herein.

The term “alkoxy” or “alkyloxy”, as used herein refers to a saturated(i.e., O-alkyl) or unsaturated (i.e., O-alkenyl and O-alkynyl) groupattached to the parent molecular moiety through an oxygen atom. Incertain embodiments, the alkyl group contains 1-20; 2-20; 3-20; 4-20;5-20; 6-20; 7-20 or 8-20 aliphatic carbon atoms. In certain otherembodiments, the alkyl group contains 1-10; 2-10; 3-10; 4-10; 5-10;6-10; 7-10 or 8-10 aliphatic carbon atoms. In yet other embodiments, thealkyl, alkenyl, and alkynyl groups employed in the invention contain1-8; 2-8; 3-8; 4-8; 5-8; 6-20 or 7-8 aliphatic carbon atoms. In stillother embodiments, the alkyl group contains 1-6; 2-6; 3-6; 4-6 or 5-6aliphatic carbon atoms. In yet other embodiments, the alkyl groupcontains 1-4; 2-4 or 3-4 aliphatic carbon atoms. Examples of alkoxy,include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy,n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, neopentoxy, n-hexoxy andthe like.

The term “thioalkyl” as used herein refers to a saturated (i.e.,S-alkyl) or unsaturated (i.e., S-alkenyl and S-alkynyl) group attachedto the parent molecular moiety through a sulfur atom. In certainembodiments, the alkyl group contains 1-20 aliphatic carbon atoms. Incertain other embodiments, the alkyl group contains 1-10 aliphaticcarbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynylgroups employed in the invention contain 1-8 aliphatic carbon atoms. Instill other embodiments, the alkyl group contains 1-6 aliphatic carbonatoms. In yet other embodiments, the alkyl group contains 1-4 aliphaticcarbon atoms. Examples of thioalkyl include, but are not limited to,methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and thelike.

The term “alkylamino” refers to a group having the structure —NHR′wherein R′ is aliphatic or alicyclic, as defined herein. The term“aminoalkyl” refers to a group having the structure NH₂R′—, wherein R′is aliphatic or alicyclic, as defined herein. In certain embodiments,the aliphatic or alicyclic group contains 1-20 aliphatic carbon atoms.In certain other embodiments, the aliphatic or alicyclic group contains1-10 aliphatic carbon atoms. In still other embodiments, the aliphaticor alicyclic group contains 1-6 aliphatic carbon atoms. In yet otherembodiments, the aliphatic or alicyclic group contains 1-4 aliphaticcarbon atoms. In yet other embodiments, R′ is an alkyl, alkenyl, oralkynyl group containing 1-8 aliphatic carbon atoms. Examples ofalkylamino include, but are not limited to, methylamino, ethylamino,iso-propylamino and the like.

Some examples of substituents of the above-described aliphatic (andother) moieties of compounds of the invention include, but are notlimited to aliphatic; alicyclic; heteroaliphatic; heterocyclic;aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl;alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy;heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F;Cl; Br; I; —OH; —NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH;—CH₂NH₂; —CH₂SO₂CH₃; —C(═O)R_(x); —CO₂(R_(x)); —C(═O)N(R_(x))₂;—OC(═O)R_(x); —OCO₂R_(x); —OC(═O)N(R_(x))₂; —N(R_(x))₂; —OR_(x);—SR_(x); —S(O)R_(x); —S(O)₂R_(x); —NR_(x)(CO)R_(x); —N(R_(x))CO₂R_(x);—N(R_(x))S(O)₂R_(x); —N(R_(x))C(═O)N(R_(x))₂; —S(O)₂N(R_(x))₂; whereineach occurrence of R_(x) independently includes, but is not limited to,aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl,alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl,wherein any of the aliphatic, alicyclic, heteroaliphatic, heterocyclic,alkylaryl, or alkylheteroaryl substituents described above and hereinmay be substituted or unsubstituted, branched or unbranched, saturatedor unsaturated, and wherein any of the aryl or heteroaryl substituentsdescribed above and herein may be substituted or unsubstituted.Additional examples of generally applicable substituents are illustratedby the specific embodiments shown in the Examples that are describedherein.

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine, chlorine, bromine and iodine.

The term “haloalkyl” denotes an alkyl group, as defined above, havingone, two, or three halogen atoms attached thereto and is exemplified bysuch groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.

The term “amino”, as used herein, refers to a primary (—NH₂), secondary(—NHR_(x)), tertiary (—NR_(x)R_(y)) or quaternary (—N⁺R_(x)R_(y)R_(z))amine, where R_(x), R_(y) and R_(z) are independently an aliphatic,alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromaticmoiety, as defined herein. Examples of amino groups include, but are notlimited to, methylamino, dimethylamino, ethylamino, diethylamino,diethylaminocarbonyl, methylethylamino, i so-propyl amino, piperidino,trimethylamino, and propylamino.

The term “acyl”, as used herein, refers to a group having the generalformula —C(═O)R, where R is an aliphatic, alicyclic, heteroaliphatic,heterocyclic, aromatic or heteroaromatic moiety, as defined herein.

The term “C₂₋₆alkenylene”, as used herein, refers to a substituted orunsubstituted, linear or branched unsaturated divalent radicalconsisting solely of carbon and hydrogen atoms, having from two to sixcarbon atoms, having a free valence “-” at both ends of the radical, andwherein the unsaturation is present only as double bonds and wherein adouble bond can exist between the first carbon of the chain and the restof the molecule.

As used herein, the terms “aliphatic”, “heteroaliphatic”, “alkyl”,“alkenyl”, “alkynyl”, “heteroalkyl”, “heteroalkenyl”, “heteroalkynyl”,and the like encompass substituted and unsubstituted, saturated andunsaturated, and linear and branched groups. Similarly, the terms“alicyclic”, “heterocyclic”, “heterocycloalkyl”, “heterocycle” and thelike encompass substituted and unsubstituted, and saturated andunsaturated groups. Additionally, the terms “cycloalkyl”,“cycloalkenyl”, “cycloalkynyl”, “heterocycloalkyl”,“heterocycloalkenyl”, “heterocycloalkynyl”, “aromatic”,“heteroaromatic”, “aryl”, “heteroaryl” and the like encompass bothsubstituted and unsubstituted groups.

The phrase, “pharmaceutically acceptable derivative”, as used herein,denotes any pharmaceutically acceptable salt, ester, or salt of suchester, of such compound, or any other adduct or derivative which, uponadministration to a patient, is capable of providing (directly orindirectly) a compound as otherwise described herein, or a metabolite orresidue thereof. Pharmaceutically acceptable derivatives thus includeamong others pro-drugs. A pro-drug is a derivative of a compound,usually with significantly reduced pharmacological activity, whichcontains an additional moiety, which is susceptible to removal in vivoyielding the parent molecule as the pharmacologically active species. Anexample of a pro-drug is an ester, which is cleaved in vivo to yield acompound of interest. Another example is an N-methyl derivative of acompound, which is susceptible to oxidative metabolism resulting inN-demethylation. Pro-drugs of a variety of compounds, and materials andmethods for derivatizing the parent compounds to create the pro-drugs,are known and may be adapted to the present invention. Certain exemplarypharmaceutical compositions and pharmaceutically acceptable derivativeswill be discussed in more detail herein below.

The term “tautomerization” refers to the phenomenon wherein a proton ofone atom of a molecule shifts to another atom. See, Jerry March,Advanced Organic Chemistry: Reactions, Mechanisms and Structures, FourthEdition, John Wiley & Sons, pages 69-74 (1992). The term “tautomer” asused herein, refers to the compounds produced by the proton shift.

By the term “protecting group”, as used herein, it is meant that aparticular functional moiety, e.g., O, S, or N, is temporarily blockedso that a reaction can be carried out selectively at another reactivesite in a multifunctional compound. In preferred embodiments, aprotecting group reacts selectively in good yield to give a protectedsubstrate that is stable to the projected reactions; the protectinggroup must be selectively removed in good yield by readily available,preferably nontoxic reagents that do not attack the other functionalgroups; the protecting group forms an easily separable derivative (morepreferably without the generation of new stereogenic centers); and theprotecting group has a minimum of additional functionality to avoidfurther sites of reaction. As detailed herein, oxygen, sulfur, nitrogenand carbon protecting groups may be utilized. For example, in certainembodiments, as detailed herein, certain exemplary oxygen protectinggroups are utilized. These oxygen protecting groups include, but are notlimited to methyl ethers, substituted methyl ethers (e.g., MOM(methoxymethyl ether), MTM (methylthiomethyl ether), BOM(benzyloxymethyl ether), PMBM or MPM (p-methoxybenzyloxymethyl ether),to name a few), substituted ethyl ethers, substituted benzyl ethers,silyl ethers (e.g., TMS (trimethylsilyl ether), TES(triethylsilylether), TIPS (triisopropylsilyl ether), TBDMS(t-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS(t-butyldiphenyl silyl ether), to name a few), esters (e.g., formate,acetate, benzoate (Bz), trifluoroacetate, dichloroacetate, to name afew), carbonates, cyclic acetals and ketals. In certain other exemplaryembodiments, nitrogen protecting groups are utilized. These nitrogenprotecting groups include, but are not limited to, carbamates (includingmethyl, ethyl and substituted ethyl carbamates (e.g., Troc), to name afew) amides, cyclic imide derivatives, N-alkyl and N-aryl amines, iminederivatives, and enamine derivatives, to name a few. Certain otherexemplary protecting groups are detailed herein, however, it will beappreciated that the present invention is not intended to be limited tothese protecting groups; rather, a variety of additional equivalentprotecting groups can be readily identified using the above criteria andutilized in the present invention. Additionally, a variety of protectinggroups are described in “Protective Groups in Organic Synthesis” ThirdEd. Greene, T. W. and Wuts, P. G., Eds., John Wiley & Sons, New York:1999, the entire contents of which are hereby incorporated by reference.

As used herein, the term “isolated” when applied to the compounds of thepresent invention, refers to such compounds that are (i) separated fromat least some components with which they are associated in nature orwhen they are made and/or (ii) produced, prepared or manufactured by thehand of man.

As used herein the term “biological sample” includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from an animal (e.g., mammal) or extracts thereof; and blood,saliva, urine, feces, semen, tears, or other body fluids or extractsthereof; or purified versions thereof. For example, the term “biologicalsample” refers to any solid or fluid sample obtained from, excreted byor secreted by any living organism, including single-celledmicroorganisms (such as bacteria and yeasts) and multicellular organisms(such as plants and animals, for instance a vertebrate or a mammal, andin particular a healthy or apparently healthy human subject or a humanpatient affected by a condition or disease to be diagnosed orinvestigated). The biological sample can be in any form, including asolid material such as a tissue, cells, a cell pellet, a cell extract,cell homogenates, or cell fractions; or a biopsy, or a biological fluid.The biological fluid may be obtained from any site (e.g. blood, saliva(or a mouth wash containing buccal cells), tears, plasma, serum, urine,bile, seminal fluid, cerebrospinal fluid, amniotic fluid, peritonealfluid, and pleural fluid, or cells therefrom, aqueous or vitreous humor,or any bodily secretion), a transudate, an exudate (e.g. fluid obtainedfrom an abscess or any other site of infection or inflammation), orfluid obtained from a joint (e.g. a normal joint or a joint affected bydisease such as rheumatoid arthritis, osteoarthritis, gout or septicarthritis). The biological sample can be obtained from any organ ortissue (including a biopsy or autopsy specimen) or may comprise cells(whether primary cells or cultured cells) or medium conditioned by anycell, tissue or organ. Biological samples may also include sections oftissues such as frozen sections taken for histological purposes.Biological samples also include mixtures of biological moleculesincluding proteins, lipids, carbohydrates and nucleic acids generated bypartial or complete fractionation of cell or tissue homogenates.Although the sample is preferably taken from a human subject, biologicalsamples may be from any animal, plant, bacteria, virus, yeast, etc. Theterm animal, as used herein, refers to humans as well as non-humananimals, at any stage of development, including, for example, mammals,birds, reptiles, amphibians, fish, worms and single cells. Cell culturesand live tissue samples are considered to be pluralities of animals. Incertain exemplary embodiments, the non-human animal is a mammal (e.g., arodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep,cattle, a primate, or a pig). An animal may be a transgenic animal or ahuman clone. If desired, the biological sample may be subjected topreliminary processing, including preliminary separation techniques.

BRIEF DESCRIPTIONS OF THE FIGURES

FIG. 1 shows the inhibition of CYP11B1 and CYP11B2 by a compound of theinvention;

FIG. 2 A-D show the effect of a compound of the invention in a renalinjury model;

FIG. 3 shows the effect of a compound of the invention on blood pressurein the 5/6 nephrectomy model;

FIG. 4 A-D show the effect of a compound of the invention on renalinjury in the 5/6 nephrectomy model;

FIG. 5 shows the effect of a compound of the invention on renalhistology in the 5/6 nephrectomy model;

FIG. 6 A-B show the effect of a compound on kidney weight as percent ofbody weight (A) and as a percent of pre-treatment kidney weight as apercent of body weight (B) in a genetic model of polycystic kidneydisease (PCK);

FIG. 7 A-B show the effect of a compound on kidney cystic area as apercent of section area (A) and as a percent of pre-treatment cysticarea as a percent of section area (B) in a genetic model of polycystickidney disease;

FIG. 8 shows the effect of a compound on kidney collagen content asmeasured by Sirius Red staining in a genetic model of polycystic kidneydisease;

FIG. 9 shows the effect of a compound on urinary protein excretion in agenetic model of polycystic kidney disease; and

FIG. 10 shows the effect of a compound on liver collagen content asmeasured by Sirius Red staining in a genetic model of polycystic kidneydisease.

DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE INVENTION

In one embodiment, certain novel inventive compounds have the structureshown in Formula (I) below:

-   -   or a salt, solvate, enantiomer, ester, or hydrate thereof;    -   wherein R¹ and R² are each independently one or more H, halogen,        haloalkyl, NO₂, CN, COOR⁵, SO₂R⁵, CONR⁵R⁶, SO₂NR⁵R⁶, NR⁵R⁶, OR⁵,        alkyl, alkenyl, alkynyl, heteroalkyl, aryl or hetero aryl, any        of which is further substituted by one or more R⁷; or two R²        substituents taken together with the respective carbon atoms to        which they are attached, form a 5-6 membered heterocyclic ring,        wherein said ring is optionally substituted with one or more R⁷;    -   R³ is H, alkyl, alkenyl or alkynyl, any of which is further        substituted by one or more R⁷;    -   R⁴ is H, NR⁵R⁶, SR⁵, or OR⁵;    -   R⁵ and R⁶ are independently hydrogen, alkyl, aryl, heteroaryl or        haloalkyl;    -   R⁷ is H, halogen, alkyl, haloalkyl, NO₂, CN, COOR⁸, SO₂R⁸,        CONR⁸R⁹, SO₂NR⁸R⁹, NR⁸R⁹, or OR⁸; and    -   R⁸ and R⁹ are independently hydrogen, alkyl or haloalkyl.

In certain embodiments, each R¹ is independently hydrogen, fluoro,chloro, bromo, phenyl, pyridyl, isopropyl, methoxy, ethyoxy, 1-propyloxyor 2-propyloxy.

In certain embodiments, R¹ is 1-propyloxy or 2-propyloxy.

In certain embodiments, R¹ is hydrogen.

In certain embodiments, R¹ is fluoro.

In certain embodiments, R¹ is chloro.

In certain embodiments, R¹ is bromo.

In certain embodiments, R¹ is phenyl.

In certain embodiments, R¹ is pyridyl.

In certain embodiments, R¹ is isopropyl.

In certain embodiments, R¹ is methoxy.

In certain embodiments, R¹ is ethyoxy.

In certain embodiments, R¹ is 2-propyloxy.

In certain embodiments, R¹ is 1-propyloxy.

In certain embodiments, each R² is independently hydrogen, fluoro,chloro, bromo, cyano, CONH₂, nitro, trifluoromethyl, diisopropylamino,trifluoromethoxy, trifluoroethoxy, methoxy or phenoxy.

In certain embodiments, R² is trifluoromethyl, trifluoromethoxy ortrifluoroethoxy.

In certain embodiments, R² is hydrogen.

In certain embodiments, R² is fluoro.

In certain embodiments, R² is chloro.

In certain embodiments, R² is bromo.

In certain embodiments, R² is cyano.

In certain embodiments, R² is CONH₂.

In certain embodiments, R² is nitro.

In certain embodiments, R² is trifluoromethyl.

In certain embodiments, R² is diisopropylamino.

In certain embodiments, R² is trifluoromethoxy.

In certain embodiments, R² is methoxy.

In certain embodiments, R² is phenoxy.

In certain embodiments R² is (4-fluoro)phenoxy.

In certain embodiments R² is (4-trifluoromethoxy)phenoxy.

In certain embodiments, two R² substituents taken together with therespective carbon atoms to which they are attached, form a 5-6 memberedheterocyclic ring, wherein said ring is optionally substituted with oneor more R⁷.

In one embodiment, two R² substituents taken together with therespective carbon atoms to which they are attached is methylenedioxy,optionally further substituted with difluoro.

In certain embodiments, R² represents di-substitution with two samesubstituents such as difluoro, dichloro, dibromo, dimethyl, dimethoxy,ditrifluoromethyl, ditrifluoroethoxy and ditrifluoromethoxy.

In certain embodiments, R² is difluoro.

In certain embodiments, R² is dichloro.

In certain embodiments, R² is dibromo.

In certain embodiments, R² is dimethyl.

In certain embodiments, R² is dimethoxy.

In certain embodiments, R² is ditrifluoromethyl.

In certain embodiments, R² is ditrifluoromethoxy.

In certain embodiments, R² is ditrifluoroethoxy.

In certain embodiments, R² represents di-substitution with two differentsubstituents such as fluoro and chloro, fluoro and bromo, fluoro andmethoxy, chloro and methoxy, bromo and methoxy, methyl and methoxy,trifluoromethyl and methoxy, trifluoromethoxy and methoxy, fluoro andtrifluoromethyl, chloro and trifluoromethyl, bromo and trifluoromethyl,methyl and trifluoromethyl, trifluoromethoxy and trifluoromethyl, fluoroand trifluoromethoxy, chloro and trifluoromethoxy, bromo andtrifluoromethoxy, methyl and trifluoromethoxy, trifluoromethyl andtrifluoromethoxy, fluoro and trifluoroethoxy, chloro andtrifluoroethoxy, bromo and trifluoroethoxy, methyl and trifluoroethoxy,trifluoromethoxy and trifluoroethoxy or trifluoromethyl andtrifluoroethoxy.

In certain embodiments, R² are fluoro and chloro.

In certain embodiments, R² are fluoro and bromo.

In certain embodiments, R² are fluoro and methoxy.

In certain embodiments, R² are chloro and methoxy.

In certain embodiments, R² are bromo and methoxy.

In certain embodiments, R² are methyl and methoxy.

In certain embodiments, R² are trifluoromethyl and methoxy.

In certain embodiments, R² are trifluoromethyl and methoxy.

In certain embodiments, R² are fluoro and trifluoromethyl.

In certain embodiments, R² are chloro and trifluoromethyl.

In certain embodiments, R² are bromo and trifluoromethyl.

In certain embodiments, R² are methyl and trifluoromethyl.

In certain embodiments, R² are trifluoromethoxy and trifluoromethyl.

In certain embodiments, R² are fluoro and trifluoromethoxy.

In certain embodiments, R² are chloro and trifluoromethoxy.

In certain embodiments, R² are bromo and trifluoromethoxy.

In certain embodiments, R² are methyl and trifluoromethoxy.

In certain embodiments, R² are trifluoromethyl and trifluoromethoxy.

In certain embodiments, R² are fluoro and trifluoroethoxy.

In certain embodiments, R² are chloro and trifluoroethoxy.

In certain embodiments, R² are bromo and trifluoroethoxy.

In certain embodiments, R² are methyl and trifluoroethoxy.

In certain embodiments, R² are trifluoromethoxy and trifluoroethoxy.

In certain embodiments, R² are trifluoromethyl and trifluoroethoxy.

In certain embodiments, R² represents tri-substitution with three samesubstituents such as trifluoro, trichloro or tribromo.

In certain embodiments, R² is trifluoro.

In certain embodiments, R² is trichloro.

In certain embodiments, R² is tribromo.

In certain embodiments, R² represents tri-substitution with differentsubstituents such as difluoro and chloro, difluoro and bromo, difluoroand trifluoromethyl, difluoro and trifluoromethoxy, difluoro andtrifluoroethoxy, dichloro and fluoro, dichloro and bromo, dichloro andtrifluoromethyl, dichloro and trifluoromethoxy, dichloro andtrifluoroethoxy, dibromo and fluoro, dibromo and chloro, dibromo andtrifluoromethyl, dibromo and trifluoromethoxy, and dibromo andtrifluoroethoxy.

In certain embodiments, R² are difluoro and chloro.

In certain embodiments, R² are difluoro and bromo.

In certain embodiments, R² are difluoro and trifluoromethyl.

In certain embodiments, R² are difluoro and trifluoromethoxy.

In certain embodiments, R² are difluoro and trifluoroethoxy.

In certain embodiments, R² are dichloro and fluoro.

In certain embodiments, R² are dichloro and bromo.

In certain embodiments, R² are dichloro and trifluoromethyl.

In certain embodiments, R² are dichloro and trifluoromethoxy.

In certain embodiments, R² are dichloro and trifluoroethoxy.

In certain embodiments, R² are dibromo and fluoro.

In certain embodiments, R² are dibromo and chloro.

In certain embodiments, R² are dibromo and trifluoromethyl.

In certain embodiments, R² are dibromo and trifluoromethoxy.

In certain embodiments, R² are dibromo and trifluoroethoxy.

In certain embodiments, R² are chloro, bromo and trifluoromethyl.

In certain embodiments, R² are chloro, bromo and trifluoromethoxy.

In certain embodiments, R³ is hydrogen, methyl, ethyl, 1-propyl,2-propyl, cyclopropyl, isobutyl or t-butyl.

In certain embodiments, R³ is hydrogen.

In certain embodiments, R³ is methyl.

In certain embodiments, R³ is ethyl.

In certain embodiments, R³ is 1-propyl.

In certain embodiments, R³ is 2-propyl.

In certain embodiments, R³ is cyclopropyl.

In certain embodiments, R³ is isobutyl.

In certain embodiments, R³ is t-butyl.

In certain embodiments, R⁴ is hydrogen, SH, NH₂ or OH.

In certain embodiments, R⁴ is hydrogen.

In certain embodiments, R⁴ is SH.

In certain embodiments, R⁴ is NH₂.

In certain embodiments, R⁴ is OH.

In certain embodiments, enantiomers of the aforementioned compounds areprovided, such that, for example, the definitions of substituents R³ andR⁴ are reversed.

In Formula (I), “one or more” means 1, 2, 3, or 4 independentsubstituents. As noted herein, when two or more R¹ or R² substituentsare present that are not hydrogen, they may be the same or different, ora combination of two or more that are the same and one or more that isdifferent.

The above Formula (I) is shown without a definitive stereochemistry atcertain positions. The present invention includes all stereoisomers ofFormula (I) and pharmaceutically acceptable salts thereof. Further,mixtures of stereoisomers as well as isolated specific stereoisomers arealso included. During the course of the synthetic procedures used toprepare such compounds, or in using racemization or epimerizationprocedures known to those skilled in the art, the products of suchprocedures can be mixture of stereoisomers.

Moreover, some of the foregoing compounds can comprise one or moreasymmetric centers, and thus can exist in various isomeric forms, e.g.,stereoisomers and/or diastereomers. Thus, inventive compounds andpharmaceutical compositions thereof may be in the form of an individualenantiomer, diastereomer or geometric isomer, or may be in the form of amixture of stereoisomers. In certain embodiments, the compounds of theinvention are enantiopure compounds. In certain other embodiments,mixtures of stereoisomers or diastereomers are provided.

It will be appreciated that for each of the embodiments described aboveand herein, any one or more occurrences of aliphatic and/orheteroaliphatic may independently be substituted or unsubstituted,linear or branched, saturated or unsaturated; any one or moreoccurrences of alicyclic and/or heteroalicyclic may independently besubstituted or unsubstituted, saturated or unsaturated; and any one ormore occurrences of aryl and/or heteroaryl may independently besubstituted or unsubstituted.

Furthermore, certain compounds, as described herein may have one or moredouble bonds that can exist as either the Z or E isomer, unlessotherwise indicated. The invention additionally encompasses thecompounds as individual isomers substantially free of other isomers andalternatively, as mixtures of various isomers, e.g., racemic mixtures ofstereoisomers. In addition to the above-mentioned compounds per se, thisinvention also encompasses pharmaceutically acceptable derivatives ofthese compounds and compositions comprising one or more compounds of theinvention and one or more pharmaceutically acceptable excipients oradditives.

Compounds of the invention may be prepared by crystallization ofcompound of Formula (I) under different conditions and may exist as oneor a combination of polymorphs of compound of general formula (I)forming part of this invention. For example, different polymorphs may beidentified and/or prepared using different solvents, or differentmixtures of solvents for recrystallization; by performingcrystallizations at different temperatures; or by using various modes ofcooling, ranging from very fast to very slow cooling duringcrystallizations. Polymorphs may also be obtained by heating or meltingthe compound followed by gradual or fast cooling. The presence ofpolymorphs may be determined by solid probe NMR spectroscopy, IRspectroscopy, differential scanning calorimetry, powder X-raydiffractogram and/or other techniques. Thus, the present inventionencompasses inventive compounds, their derivatives, their tautomeric andgeometrical isomeric forms, their stereoisomers, their positionalisomer, their polymorphs, their pharmaceutically acceptable salts theirpharmaceutically acceptable solvates and pharmaceutically acceptablecompositions containing them. Tautomeric forms of compounds of thepresent invention include, pyrazoles, pyridones and enols, etc., andgeometrical isomers include E/Z isomers of compounds having double bondsand cis-trans isomers of monocyclic or fused ring systems, etc.

Nonlimiting examples of compounds of Formula (I) include1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)-2-methylpropan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(pyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-2,2-dimethyl-1-(pyridin-3-yl)propan-1-ol;(6-bromobenzo[d]thiazol-2-yl)(cyclopropyl)(pyridin-3-yl)methanol;1-(6-bromobenzo[d]thiazol-2-yl)-3-methyl-1-(pyridin-3-yl)butan-1-ol;1-(benzo[d]thiazol-2-yl)-1-(pyridin-3-yl)butan-1-ol;1-(5-bromobenzo[d]thiazol-2-yl)-2-methyl-1-(pyridin-3-yl)propan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-2-methyl-1-(pyridin-3-yl)propan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-2-methyl-1-(pyridin-3-yl)propan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(pyridin-3-yl)propan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-2-methyl-1-(pyridin-3-yl)propan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(pyridin-3-yl)ethanol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-chloropyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-bromopyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-phenylpyridin-3-yl)butan-1-ol;1-(5-bromobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol;1-(5-(diisopropylamino)benzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol;1-(6-fluorobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol;1-([3,3′-bipyridin]-5-yl)-1-(6-bromobenzo[d]thiazol-2-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(pyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(6-methoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2-methylpropan-1-ol;(6-bromobenzo[d]thiazol-2-yl)(4-methoxypyridin-3-yl)methanol;(7-bromobenzo[d]thiazol-2-yl)(4-methoxypyridin-3-yl)methanol;1-(4-methoxypyridin-3-yl)-1-(6-nitrobenzo[d]thiazol-2-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(benzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2,2-dimethylpropan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)-2-methylpropan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)-2-methylpropan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)-2-methylpropan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-isopropoxypyridin-3-yl)-2-methylpropan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-isopropoxypyridin-3-yl)-2-methylpropan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)butan-1-ol;1-(6-chlorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-nitrobenzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-fluorobenzo[d]thiazol-2-yl)butan-1-ol;1-(7-chiorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4,7-difluorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(7-methoxybenzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(7-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-methoxybenzo[d]thiazol-2-yl)butan-1-ol;1-(4-isopropoxypyridin-3-yl)-1-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(5,6-dichlorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4-propoxypyridin-3-yl)-1-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(2,2-difluoro-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]thiazol-6-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2-methylpropan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(4-(trifluoromethoxy)phenoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(4-fluorophenoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(5-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(7-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(5-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(7-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(5-methyl-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(7-methyl-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;(R)-1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethoxy)-7-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;(R)-1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;(S)-1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethoxy)-7-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;(S)-1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethoxy)-5-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(7-methoxy-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-propoxypyridin-3-yl)-1-(6-(trifluoromethoxy)-5-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;1-4propoxypyridin-3-yl)-1-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;1-(5,6-bis(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(5-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(6,7-bis(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxy-5-methoxypyridin-3-yl)butan-1-ol;1-(7-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxy-5-methoxypyridin-3-yl)butan-1-ol;1-(7-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxy-5-methoxypyridin-3-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(5-fluoro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(5-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(7-chioro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(6-bromo-5,7-dichlorobenzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(4-propoxypyridin-3-yl)-1-(5,6,7-trichlorobenzo[d]thiazol-2-yl)butan-1-ol;1-(5,7-dichloro-6-(2,2,2-trifluoroethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(7-chloro-6-(2,2,2-trifluoroethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(5-chloro-6-(2,2,2-trifluoroethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(5,7-difluoro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(5,7-dichloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2-methylpropan-1-ol;1-(6-cyanobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;2-(1-(4-ethoxypyridin-3-yl)-1-hydroxybutyl)benzo[d]thiazole-6-carboxamide;and 1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol.

2) Pharmaceutical Compositions

As discussed above this invention provides novel compounds that havebiological properties useful for the treatment of any of a number ofconditions or diseases in which an aldosterone level lowering agent hasa therapeutically useful role, or reduction in fibrosis istherapeutically beneficial.

Accordingly, in another aspect of the present invention, pharmaceuticalcompositions are provided, which comprise any one or more of thecompounds described herein (or a prodrug, pharmaceutically acceptablesalt or other pharmaceutically acceptable derivative thereof), andoptionally comprise a pharmaceutically acceptable carrier. In certainembodiments, these compositions optionally further comprise one or moreadditional therapeutic agents. Alternatively, a compound of thisinvention may be administered to a patient in need thereof incombination with the administration of one or more other therapeuticagents. For example, additional therapeutic agents for conjointadministration or inclusion in a pharmaceutical composition with acompound of this invention may be an approved agent to treat the same orrelated indication, or it may be any one of a number of agentsundergoing approval in the Food and Drug Administration that ultimatelyobtain approval for the treatment of any disorder related to fibrosis.It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable salts, esters, saltsof such esters, or a pro-drug or other adduct or derivative of acompound of this invention which upon administration to a patient inneed is capable of providing, directly or indirectly, a compound asotherwise described herein, or a metabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts of amines, carboxylic acids, and other types ofcompounds, are well known in the art. For example, S. M. Berge, et al.describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein byreference. The salts can be prepared in situ during the final isolationand purification of the compounds of the invention, or separately byreacting a free base or free acid function with a suitable reagent, asdescribed generally below. For example, a free base function can bereacted with a suitable acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may, include metal salts such as alkali metal salts, e.g.sodium or potassium salts; and alkaline earth metal salts, e.g. calciumor magnesium salts. Examples of pharmaceutically acceptable, nontoxicacid addition salts are salts of an amino group formed with inorganicacids such as hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid and perchloric acid or with organic acids such as aceticacid, oxalic acid, maleic acid, tartaric acid, citric acid, succinicacid or malonic acid or by using other methods used in the art such asion exchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

Additionally, as used herein, the term “pharmaceutically acceptableester” refers to esters that hydrolyze in vivo and include those thatbreak down readily in the human body to leave the parent compound or asalt thereof. Suitable ester groups include, for example, those derivedfrom pharmaceutically acceptable aliphatic carboxylic acids,particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, inwhich each alkyl or alkenyl moiety advantageously has not more than 6carbon atoms. Examples of particular esters include formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

Furthermore, the term “pharmaceutically acceptable prodrugs” as usedherein refers to those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the issues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “prodrug” refers tocompounds that are rapidly transformed in vivo to yield the parentcompound of the above formula, for example by hydrolysis in blood, orN-demethylation of a compound of the invention where R¹ is methyl. Athorough discussion is provided in T. Higuchi and V. Stella, Pro-drugsas Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, andin Edward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated herein by reference. By way of other examples, carbamateand amide prodrugs of compounds of formulae (I)-(IV) are embodiedherein, such as those discussed in Rautio et al., 2008, Nature Rev DrugDiscov 7:255-70; Jordan et al., 2003, Bioorg Med Chem 10:2625-33 and Hayet al., 2003, J Med Chem 46:5533-45, by way of non-limiting examples.

As described above, the pharmaceutical compositions of the presentinvention additionally comprise a pharmaceutically acceptable carrier,which, as used herein, includes any and all solvents, diluents, or otherliquid vehicle, dispersion or suspension aids, surface active agents,isotonic agents, thickening or emulsifying agents, preservatives, solidbinders, lubricants and the like, as suited to the particular dosageform desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses variouscarriers used in formulating pharmaceutical compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutical composition, its use is contemplatedto be within the scope of this invention. Some examples of materialswhich can serve as pharmaceutically acceptable carriers include, but arenot limited to, sugars such as lactose, glucose and sucrose; starchessuch as corn starch and potato starch; cellulose and its derivativessuch as sodium carboxymethyl cellulose, ethyl cellulose and celluloseacetate; powdered tragacanth; malt; gelatine; talc; excipients such ascocoa butter and suppository waxes; oils such as peanut oil, cottonseedoil; safflower oil, sesame oil; olive oil; corn oil and soybean oil;glycols; such as propylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut (peanut), corn, germ, olive, castor, and sesameoils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols andfatty acid esters of sorbitan, and mixtures thereof. Besides inertdiluents, the oral compositions can also include adjuvants such aswetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension orcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionthat, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose and starch. Such dosage forms may alsocomprise, as in normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such asmagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

In other embodiments solid dosage forms are provided. In certainembodiments, such solid dosage forms provide a higher than about a 20%oral bioavailability. As will be shown in the examples below, compoundsof the invention can be co-precipitated with one or more agents such asmannitol, a combination of mannitol and lactobionic acid, a combinationof mannitol and gluconic acid, a combination of mannitol andmethanesulfonic acid, a combination of microcrystalline cellulose andoleic acid or a combination of pregelatinized starch and oleic acid. Theforegoing examples of one or more agents to aid in preparingformulations of inventive compound are merely illustrative andnon-limiting. Non-limiting examples of inventive compounds in such soliddosage forms include

The present invention encompasses pharmaceutically acceptable topicalformulations of inventive compounds. The term “pharmaceuticallyacceptable topical formulation”, as used herein, means any formulationwhich is pharmaceutically acceptable for intradermal administration of acompound of the invention by application of the formulation to theepidermis. In certain embodiments of the invention, the topicalformulation comprises a carrier system. Pharmaceutically effectivecarriers include, but are not limited to, solvents (e.g., alcohols, polyalcohols, water), creams, lotions, ointments, oils, plasters, liposomes,powders, emulsions, microemulsions, and buffered solutions (e.g.,hypotonic or buffered saline) or any other carrier known in the art fortopically administering pharmaceuticals. A more complete listing ofart-known carriers is provided by reference texts that are standard inthe art, for example, Remington's Pharmaceutical Sciences, 16th Edition,1980 and 17th Edition, 1985, both published by Mack Publishing Company,Easton, Pa., the disclosures of which are incorporated herein byreference in their entireties. In certain other embodiments, the topicalformulations of the invention may comprise excipients. Anypharmaceutically acceptable excipient known in the art may be used toprepare the inventive pharmaceutically acceptable topical formulations.Examples of excipients that can be included in the topical formulationsof the invention include, but are not limited to, preservatives,antioxidants, moisturizers, emollients, buffering agents, solubilizingagents, other penetration agents, skin protectants, surfactants, andpropellants, and/or additional therapeutic agents used in combination tothe inventive compound. Suitable preservatives include, but are notlimited to, alcohols, quaternary amines, organic acids, parabens, andphenols. Suitable antioxidants include, but are not limited to, ascorbicacid and its esters, sodium bisulfite, butylated hydroxytoluene,butylated hydroxyanisole, tocopherols, and chelating agents like EDTAand citric acid. Suitable moisturizers include, but are not limited to,glycerine, sorbitol, polyethylene glycols, urea, and propylene glycol.Suitable buffering agents for use with the invention include, but arenot limited to, citric, hydrochloric, and lactic acid buffers. Suitablesolubilizing agents include, but are not limited to, quaternary ammoniumchlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.Suitable skin protectants that can be used in the topical formulationsof the invention include, but are not limited to, vitamin E oil,allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

In certain embodiments, the pharmaceutically acceptable topicalformulations of the invention comprise at least a compound of theinvention and a penetration enhancing agent. The choice of topicalformulation will depend or several factors, including the condition tobe treated, the physicochemical characteristics of the inventivecompound and other excipients present, their stability in theformulation, available manufacturing equipment, and costs constraints.As used herein the term “penetration enhancing agent” means an agentcapable of transporting a pharmacologically active compound through thestratum corneum and into the epidermis or dermis, preferably, withlittle or no systemic absorption. A wide variety of compounds have beenevaluated as to their effectiveness in enhancing the rate of penetrationof drugs through the skin. See, for example, Percutaneous PenetrationEnhancers, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., BocaRaton, Fla. (1995), which surveys the use and testing of various skinpenetration enhancers, and Buyuktimkin et al., Chemical Means ofTransdermal Drug Permeation Enhancement in Transdermal and Topical DrugDelivery Systems, Gosh T. K., Pfister W. R., Yum S. I. (Eds.),Interpharm Press Inc., Buffalo Grove, Ill. (1997). In certain exemplaryembodiments, penetration agents for use with the invention include, butare not limited to, triglycerides (e.g., soybean oil), aloe compositions(e.g., aloe-vera gel), ethyl alcohol, isopropyl alcohol,octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400,propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g.,isopropyl myristate, methyl laurate, glycerol monooleate, and propyleneglycol monooleate) and N-methyl pyrrolidone.

In certain embodiments, the compositions may be in the form ofointments, pastes, creams, lotions, gels, powders, solutions, sprays,inhalants or patches. In certain exemplary embodiments, formulations ofthe compositions according to the invention are creams, which mayfurther contain saturated or unsaturated fatty acids such as stearicacid, palmitic acid, oleic acid, palmito-oleic acid, cetyl or oleylalcohols, stearic acid being particularly preferred. Creams of theinvention may also contain a non-ionic surfactant, for example,polyoxy-40-stearate. In certain embodiments, the active component isadmixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Formulations for intraocularadministration are also included. Additionally, the present inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms are made by dissolving or dispensing the compound inthe proper medium. As discussed above, penetration enhancing agents canalso be used to increase the flux of the compound across the skin. Therate can be controlled by either providing a rate controlling membraneor by dispersing the compound in a polymer matrix or gel.

It will also be appreciated that the compounds and pharmaceuticalcompositions of the present invention can be formulated and employed incombination therapies, that is, the compounds and pharmaceuticalcompositions can be formulated with or administered concurrently with,prior to, or subsequent to, one or more other desired therapeutics ormedical procedures. The particular combination of therapies(therapeutics or procedures) to employ in a combination regimen willtake into account compatibility of the desired therapeutics and/orprocedures and the desired therapeutic effect to be achieved. It willalso be appreciated that the therapies employed may achieve a desiredeffect for the same disorder (for example, an inventive compound may beadministered concurrently with another anti-inflammatory agent), or theymay achieve different effects (e.g., control of any adverse effects). Innon-limiting examples, one or more compounds of the invention may beformulated with at least one cytokine, growth factor or otherbiological, such as an interferon, e.g., alpha interferon, or with atleast another small molecule compound. Non-limiting examples ofpharmaceutical agents that may be combined therapeutically withcompounds of the invention include: antivirals and antifibrotics such asinterferon alpha, combination of interferon alpha and ribavirin,Lamivudine, Adefovir dipivoxil and interferon gamma; anticoagulants suchas heparin and warfarin; antiplatelets e.g., aspirin, ticlopidine andclopidogrel; other growth factors involved in regeneration, e.g., VEGFand FGF and mimetics of these growth factors; antiapoptotic agents; andmotility and morphogenic agents.

In certain embodiments, the pharmaceutical compositions of the presentinvention further comprise one or more additional therapeutically activeingredients (e.g., anti-inflammatory and/or palliative). For purposes ofthe invention, the term “Palliative” refers to treatment that is focusedon the relief of symptoms of a disease and/or side effects of atherapeutic regimen, but is not curative. For example, palliativetreatment encompasses painkillers, antinausea medications andanti-sickness drugs.

3) Research Uses, Clinical Uses, Pharmaceutical Uses and Methods ofTreatment

Renal Disease. Chronic renal dysfunction is a progressive, degenerativedisorder that ultimately results in acute renal failure and requiresdialysis as an intervention, and renal transplantation as the onlypotential cure. Initiating conditions of renal dysfunction includeischemia, diabetes, underlying cardiovascular disease, or renal toxicityassociated with certain chemotherapeutics, antibiotics, andradiocontrast agents. Most end-stage pathological changes includeextensive fibrinogenesis, epithelial atrophy, and inflammatory cellinfiltration into the kidneys.

Acute renal failure is often a complication of diseases includingdiabetes or renal ischemia, procedures such as heminephrectomy, or as aside effect of therapeutics administered to treat disease. The widelyprescribed anti-tumor drug cis-diamminedichloroplatinum (cisplatin), forexample, has side effects that include a high incidence ofnephrotoxicity and renal dysfunction, mainly in the form of renaltubular damage that leads to impaired glomerular filtration.Administration of gentamicin, an aminoglycoside antibiotic, orcyclosporin A, a potent immunosuppressive compound, causes similarnephrotoxicity. The serious side effects of these effective drugsrestrict their use. The development of agents that protect renalfunction and enhance renal regeneration after administration ofnephrotoxic drugs will be of substantial benefit to numerous patients,especially those with malignant tumors, and may allow the maximaltherapeutic potentials of these drugs to be realized. The compounds ofthe invention are beneficial for the treatment of the renal diseasesmentioned above.

Fibrotic Liver Disease: Liver fibrosis is the scarring response of theliver to chronic liver injury; when fibrosis progresses to cirrhosis,morbid complications can develop. In fact, end-stage liver fibrosis orcirrhosis is the seventh leading cause of death in the United States,and afflicts hundreds of millions of people worldwide; deaths fromend-stage liver disease in the United States are expected to triple overthe next 10-15 years, mainly due to the hepatitis C epidemic. Inaddition to the hepatitis C virus, many other forms of chronic liverinjury also lead to end-stage liver disease and cirrhosis, includingother viruses such as hepatitis B and delta hepatitis, chronicalcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions(stones in the bile duct), cholangiopathies (primary biliary cirrhosisand sclerosing cholangitis), autoimmune liver disease, and inheritedmetabolic disorders (Wilson's disease, hemochromatosis, and alpha-1antitrypsin deficiency).

Treatment of liver fibrosis has focused to date on eliminating theprimary injury. For extrahepatic obstructions, biliary decompression isthe recommended mode of treatment whereas patients with Wilson's diseaseare treated with zinc acetate. In chronic hepatitis C infection,interferon has been used as antiviral therapies with limited response:˜20% when used alone or ˜50% response when used in combination withribavirin. In addition to the low-level of response, treatment withinterferon with or without ribavirin is associated with numerous severeside effects including neutropenia, thrombocytopenia, anemia,depression, generalized fatigue and flu-like symptoms, which aresufficiently significant to necessitate cessation of therapy. Treatmentsfor other chronic liver diseases such as hepatitis B, autoimmunehepatitis and Wilson's disease are also associated with many sideeffects, while primary biliary cirrhosis, primary sclerosing cholangitisand non-alcoholic fatty liver disease have no effective treatment otherthan liver transplantation.

The advantage of treating fibrosis rather than only the underlyingetiology, is that antifibrotic therapies should be broadly applicableacross the full spectrum of chronic liver diseases. Whiletransplantation is currently the most effective cure for liver fibrosis,mounting evidence indicates that not only fibrosis, but even cirrhosisis reversible. Unfortunately patients often present with advanced stagesof fibrosis and cirrhosis, when many therapies such as antivirals can nolonger be safely used due to their side effect profile. Such patientswould benefit enormously from effective antifibrotic therapy, becauseattenuating or reversing fibrosis may prevent many late stagecomplications such as infection, ascites, and loss of liver function andpreclude the need for liver transplantation. The compounds of theinvention are beneficial for the treatment of the foregoing conditions,and generally are antifibrotic agents for this and other organ ortissues.

Hepatic Ischemia-Reperfusion Injury: Currently, transplantation is themost effective therapeutic strategy for liver fibrosis. However, inspite of the significant improvement in clinical outcome during the lastdecade, liver dysfunction or failure is still a significant clinicalproblem after transplantation surgery. Ischemia-reperfusion (IR) injuryto the liver is a major alloantigen-independent component affectingtransplantation outcome, causing up to 10% of early organ failure, andleading to the higher incidence of both acute and chronic rejection.Furthermore, given the dramatic organ shortage for transplantation,surgeons are forced to consider cadaveric or steatotic grafts or othermarginal livers, which have a higher susceptibility to reperfusioninjury. In addition to transplantation surgery, liver IR injury ismanifested in clinical situations such as tissue resections (Pringlemaneuver), and hemorrhagic shock.

The damage to the postischemic liver represents a continuum of processesthat culminate in hepatocellular injury. Ischemia activates Kupffercells, which are the main sources of vascular reactive oxygen species(ROS) formation during the initial reperfusion period. In addition toKupffer cell-induced oxidant stress, with increasing length of theischemic episode, intracellular generation of ROS by xanthine oxidaseand in particular mitochondria may also contribute to liver dysfunctionand cell injury during reperfusion. Endogenous antioxidant compounds,such as superoxide dismutase, catalase, glutathione, alphatocopherol,and beta-carotene, may all limit the effects of oxidant injury but thesesystems can quickly become overwhelmed by large quantities of ROS. Workby Lemasters and colleagues, has indicated that in addition to formationof ROS, intracellular calcium dyshomeostasis is a key contributor toliver IR injury. Cell death of hepatocytes and endothelial cells in thissetting is characterized by swelling of cells and their organelles,release of cell contents, eosinophilia, karyolysis, and induction ofinflammation, characteristic of oncotic necrosis. More recent reportsindicate that liver cells also die by apoptosis, which ismorphologically characterized by cell shrinkage, formation of apoptoticbodies with intact cell organelles and absence of an inflammatoryresponse.

Indeed, minimizing the adverse effects of IR injury could significantlyincrease the number of patients that may successfully undergo livertransplantation. Pharmacologic interventions that reduce cell deathand/or enhance organ regeneration represent a therapeutic approach toimprove clinical outcome in liver transplantation, liver surgery withvascular exclusion and trauma and can therefore reduce recipient/patientmorbidity and mortality. The compounds of the invention are beneficialfor the treatment of the foregoing conditions.

Cerebral Infarction. Stroke and cerebrovascular disease are a leadingcause of morbidity and mortality in the US: at least 600,000 Americansdevelop strokes each year, and about 160,000 of these are fatal.Research on the pathophysiological basis of stroke has produced newparadigms for prevention and treatment, but translation of theseapproaches into improved clinical outcomes has proved to be painfullyslow. Preventive strategies focus primarily on reducing or controllingrisk factors such as diabetes, hypertension, cardiovascular disease, andlifestyle; in patients with severe stenosis, carotid endarterectomy maybe indicated. Cerebral angioplasty is used investigationally, but thehigh restenosis rates observed following coronary angioplasty suggestthis approach may pose unacceptable risk for many patients. Therapeuticstrategies focus primarily on acute treatment to reduce injury in theischemic penumbra, the region of reversibly damaged tissue surroundingan infarct. Thrombolytic therapy has been shown to improve perfusion tothe ischemic penumbra, but it must be administered within three hours ofthe onset of infarction. Several neuroprotective agents that blockspecific tissue responses to ischemia are promising, but none have yetbeen approved for clinical use. While these therapeutic approaches limitdamage in the ischemic penumbra, they do not address the underlyingproblem of inadequate blood supply due to occluded arteries. Analternative strategy is to induce formation of collateral blood vesselsin the ischemic region; this occurs naturally in chronic ischemicconditions, but stimulation of vascularization via therapeuticangiogenesis has potential therapeutic benefit.

Recent advances in imaging have confirmed the pathophysiological basisof the clinical observations of evolving stroke. Analysis of impairedcerebral blood flow (CBF) in the region of an arterial occlusionsupports the hypothesis that a central region of very low CBF, theischemic core, is irreversibly damaged, but damage in surrounding orintermixed zones where CBF is of less severely reduced, the ischemicpenumbra, can be limited by timely reperfusion. The compounds of theinvention are beneficial for the treatment of the foregoing conditions.

Ischemic heart disease is a leading cause of morbidity and mortality inthe US, afflicting millions of Americans each year at a cost expected toexceed $300 billion/year. Numerous pharmacological and interventionalapproaches are being developed to improve treatment of ischemic heartdisease including reduction of modifiable risk factors, improvedrevascularization procedures, and therapies to halt progression and/orinduce regression of atherosclerosis. Atherosclerosis comprises afibrotic component, and compounds described herein are useful forprevention and treatment as well as intervention in the development ofheart failure.

Polycystic kidney disease. Autosomal recessive polycystic kidney disease(ARPKD) is a rare genetic disorder, occurring in approximately 1 in20,000 individuals. A fibrocystic disease, patients present withprogressive cystic enlargement of the kidneys and/or liver accompaniedby renal and hepatic fibrosis. With no effective drug therapy for ARPKD,approximately one-third of the population presents with need for renaland/or hepatic transplantation by the age of 10 years. The compoundsdescribed here are useful for the prevention or treatment of polycystickidney disease or autosomal recessive polycystic kidney disease.

Chronic kidney disease. As noted above, one in ten American adults havesome level of chronic kidney disease (CKD), which amounts to more than20 million US citizens. CKD occurs in both diabetic and non-diabeticnephropathies and is characterized by increasing proteinuria, decliningfunctional nephron mass and a concomitant decline in renal function(glomerular filtration rate (GRF)<60 ml/min). It is estimated that20-40% of diabetes patients progress to some form of CKD. In 2004,approximately 8 million people in the US were diagnosed with aglomerular filtration rate <60 ml/min. CKD often transitions toend-stage renal disease, a life-threatening condition requiring renalreplacement therapy. The number of patients reaching end-stage renaldisease has been increasing at an average of 7% per year over the last10 years. Worldwide, approximately 1.1 million patients are on renalreplacement therapy and this number is expected to exceed 2 million in10 years, with 0.5 million from the US. Many people will die as a resultof renal failure if renal replacement therapy is not provided. Theannual mortality rate is 20% for patients on dialysis who are waitingfor renal transplantation. The combined cost of dialysis and kidneytransplantation is estimated to exceed $1 trillion. At present, there isno treatment reverses the course of CKD. Many patients with kidneydisease benefit from antihypertensive therapy with inhibitors ofangiotensin converting enzyme (ACE) or angiotensin receptor blockers(ARBs). These drugs are usually given in concert with diuretics.However, despite initial success of ACE inhibition or ARB therapy, theirlong term therapeutic effectiveness is often limited. There continues tobe a great unmet medical need for therapies that can complement thecurrent pharmaceutical armamentarium by slowing disease progression,reversing symptoms and delaying or preventing the need for renalreplacement therapy.

The compounds of the invention are beneficial for the treatment of thechronic kidney disease as well as other forms of kidney disease.

Lung (Pulmonary) Fibrosis. Idiopathic pulmonary fibrosis (IPF) accountsfor a majority of chronic interstitial lung diseases, and has anestimated incidence rate of 10.7 cases for 100,000 per year, with anestimated mortality of 50-70%. IPF is characterized by an abnormaldeposition of collagen in the lung with an unknown etiology. Althoughthe precise sequence of the pathogenic sequelae is unknown, diseaseprogression involves epithelial injury and activation, formation ofdistinctive subepithelial fibroblast/myofibroblast foci, and excessiveextracellular matrix accumulation. The development of this pathologicalprocess is preceded by an inflammatory response, often dominated bymacrophages and lymphocytes, which is mediated by the local release ofchemoattractant factors and upregulation of cell-surface adhesionmolecules. Lung injury leads to vasodilatation and leakage of plasmaproteins into interstitial and alveolar spaces, as well as activation ofthe coagulation cascade and deposition of fibrin. Fibroblasts migrateinto this provisional fibrin matrix where they synthesize extracellularmatrix molecules. In non-pathogenic conditions, excess fibrin is usuallydegraded by plasmin, a proteinase that also has a role in the activationof matrix metalloproteinases (MMPs). Activated MMPs degradeextracellular matrix and participate in fibrin removal, resulting in theclearance of the alveolar spaces and the ultimate restoration of injuredtissues. In pathological conditions, however, these processes can leadto progressive and irreversible changes in lung architecture, resultingin progressive respiratory insufficiency and an almost universallyterminal outcome in a relatively short period of time. Fibrosis is thefinal common pathway of a variety of lung disorders, and in thiscontext, the diagnosis of pulmonary fibrosis implies the recognition ofan advanced stage in the evolution of a complex process of abnormalrepair. While many studies have focused on inflammatory mechanisms forinitiating the fibrotic response, the synthesis and degradation theextracellular matrix represent the central event of the disease. It isthis process that presents a very attractive site of therapeuticintervention.

The course of IPF is characterized by progressive respiratoryinsufficiency, leading to death within 3 to 8 years from the onset ofsymptoms. Management of interstitial lung disease in general, and inparticular idiopathic pulmonary fibrosis, is difficult, unpredictableand unsatisfactory. Attempts have been made to use anti-inflammatorytherapy to reverse inflammation, relief, stop disease progression andprolong survival. Corticosteroids are the most frequently usedanti-inflammatory agents and have been the mainstay of therapy for IPFfor more than four decades, but the efficacy of this approach isunproven, and toxicities are substantial. No studies have compareddiffering dosages or duration of corticosteroid treatment in matchedpatients. Interpretation of therapy efficacy is obscured by severalfactors including heterogeneous patient populations, inclusion ofpatients with histologic entities other than usual interstitialpneumonia, lack of objective, validated endpoints, and differentcriteria for “response.” Cytotoxic drugs such as Azathioprine andcyclophosphamide have also being used in combination with low dose oralcorticosteroids. The results of such treatments vary from no improvementto significant prolongation of survival. Overall, currently availabletreatments for lung fibrosis are sub-optimal. Potential new therapieshave emerged from the use of animal models of pulmonary fibrosis andrecent advances in the cellular and molecular biology of inflammatoryreactions. Such therapies involve the use of cytokines, oxidants andgrowth factors that are elaborated during the fibrotic reaction. Despitethe use of newer strategies for treatment, the overall prognosis forpatients with interstitial lung disease has had little quantifiablechange, and the population survival remains unchanged for the last 30years. Interferon gamma (IFN) may be effective in the treatment of IPFin some patients but its role is controversial. Literature indicatedthat IFN-gamma may be involved in small airway disease in silicoticlung. Others showed that IFN gamma mediates, bleomycin-induced pulmonaryinflammation and fibrosis. The compounds of the invention are beneficialfor the treatment of the foregoing condition, among other fibroticdiseases.

Fibrosis of the skin. Scleroderma, also known as systemic sclerosis(SSc), is a connective tissue disorder characterized by abnormalthickening and formation of scar tissue in the skin (cutaneousfibrosis), lung and other organs. Scleroderma/SSc affects many bodysystems, but is primarily characterized by thickening and tightening ofthe skin. Excessive extracellular matrix (ECM) protein (principallycollagen) deposition in the skin, lung and other organs is a hallmark ofsystemic sclerosis (SSc). Many patients who suffer from SSc also have aloss of pulmonary function. Scleroderma/SSc affects approximately400,000 to 900,000 people in the United States every year. Mortality andmorbidity in SSc are very high and are directly related to the extent offibrosis in the involved organs. According to one study, the total costattributed to scleroderma/SSc in the United States reached $1.5 billionannually. In this study, morbidity represented the major cost burden,associated with $820 million (55%) of the total costs. There is no knowncure for scleroderma/SSc and the underlying cause remains unknown,though it is attributed to having an autoimmune component.

Exemplary Assays

Efficacy of the compounds of the invention on the aforementioneddisorders and diseases or the potential to be of benefit for theprophylaxis or treatment thereof may be demonstrated in various studies,ranging from biochemical effects evaluated in vitro and effects on cellsin culture, to in-vivo models of disease, wherein direct clinicalmanifestations of the disease can be observed and measured, or whereinearly structural and/or functional events occur that are established tobe involved in the initiation or progression of the disease. Thepositive effects of the compounds of the invention have beendemonstrated in a variety of such assays and models, for a number ofdiseases and disorders. One skilled in the art can readily determinefollowing the guidance described herein whether a compound of theinvention has antifibrotic activity.

Protection Against Renal Dysfunction. Clinical model: arterialocclusion. In a mouse model of transient unilateral renal arteryocclusion, male ICR mice are anesthetized and the left renal arteryoccluded with a microvascular clamp. After 30 minutes, the clamp isremoved and the kidney allowed to reperfuse. Ten minutes intoreperfusion the nonischemic contralateral kidney is excised. Animals aretreated daily with vehicle or compound of the invention (1 mg/kg, i.p.)until the day of sacrifice. Serum creatinine, BUN and urine proteinlevels, measured at 1, 4 and 7 days postischemia are used to determinethe ability of compounds of the invention to restore function to injuredkidneys. In order to create a more severe renal injury, animals aresubjected to 45 minutes of ischemia.

Protection against HgCl₂-induced renal injury. In a study mice areinjected with a high dose of HgCl₂ (7 mg/kg, s.c.) and divided intotreatment groups. Animals in the first group receive vehicle or acompound of the invention (1 mg/kg, i.p.) on the day of toxin injectionand daily thereafter for 3 days, and are euthanized on day 4. Bloodsamples that are collected prior to HgCl₂ injection, on day 2 and on day4 are analyzed for serum creatinine. In the second group, treatment withvehicle or compound begins on the day following toxin injection (i.e.,24 h delayed treatment) and daily thereafter until day 6. Mice areeuthanized on day 7. Blood samples collected prior to HgCl₂ injection,on day 4 and day 7 are analyzed for serum creatinine and BUN. Serumcreatinine, BUN, and development of tubular necrosis are measured toindicate positive clinical activity.

Protection against ureteral obstruction. The effects of the compounds ofinvention on renal injury secondary to ureteral obstruction are examinedin a mouse model of transient unilateral renal artery occlusion. Kidneysfrom mice subject to unilateral ureteral obstruction for 2 weeks areexamined for histological evidence of injury and protection by compoundtreatment. Immunohistochemical staining is performed for fibronectin,proliferating cell nuclear antigen, and TUNEL (for an assessment ofapoptosis). Trichrome staining is also performed to assess the extent ofcollagen formation as an indication of interstitial fibrosis.

Hepatic Disease. Antifibrotic Activity in Hepatic Stellate Cells. Serumstarved (activated) LX2 cells (an immortalized human hepatic stellatecell line) that are treated with a compound of the invention show adecrease in collagen I mRNA expression, as well as expression of otherfibrotic marker genes, related to significant antifibrotic activity.Liver Disease endpoints. The rat model of thioacetamide (TAA)-inducedliver fibrosis and the rat bile duct ligation model of fibrosis showsimprovements by the compounds of the invention, in a panel of functionaland histological tests: gross morphology, mass, portal pressure,presence of ascites, enzymes (AST, ALT), collagen content, interstitialfibrosis and alpha-smooth muscle actin and MMP-2.

Cerebral infarction/stroke. Neuroprotective Effects in Brain Tissue.Cerebral infarction is induced in rats by middle cerebral arteryocclusion (MCAO) for 24 hr. Test compound or vehicle is administered byi.p. at 2 mg/kg at −24, 0, and 8 hr. Sections of the brain are thenexamined for cell death by staining with a tetrazolium compound(2,3,5-triphenyl-2H-tetrazolium chloride, or TTC). Normal rat brainsexhibit a red staining due to TTC reduction whereas areas containingdead cells are white.

Lung fibrosis. In order to assess the effects of inventive compounds onpulmonary fibrosis a well-established mouse model of bleomycin-inducedlung injury is used. Male C57BL/6 mice (20-30 g, n=10/group) are treatedwith bleomycin (0.06 U/20 gram body weight) or saline via intratrachealadministration. Bleomycin-treated mice are divided into 2 groups.Compounds of the invention or vehicle is administered daily untilsacrifice on day 12 or day 20. Lung samples from the mice are thenharvested for analysis. Tissues are sectioned and stained with modifiedMasson's Trichrome and are analyzed for interstitial fibrosis. TheAshcroft scale is used to obtain a numerical fibrotic score with eachspecimen being scored independently by two histopathologists, and themean of their individual scores considered as the fibrotic score. Lungweight and hydroxyproline content are also measured as a means to assessthe extent of fibrosis.

Scleroderma. A model is used in which bleomycin is subcutaneouslyinjected into the skin is conducted in mice. Dermal hydroxyproline,dermal collagen, and dermal thickness are measures of the extent ofpathology.

Pharmaceutical Uses and Methods of Treatment

As discussed above, certain of the compounds as described herein exhibitactivity generally as aldosterone lowering agents. More specifically,compounds of the invention demonstrate the ability to treat diseases,conditions and symptoms resulting from increased or elevated aldosteronelevels. Thus, in certain embodiments, compounds of the invention areuseful for the treatment of any of a number of conditions or diseases inwhich inhibitors of aldosterone synthesis have a therapeutically usefulrole, in particular renal diseases and hypertension.

In certain embodiments, the method involves the administration of atherapeutically effective amount of the compound or a pharmaceuticallyacceptable derivative thereof to a subject (including, but not limitedto a human or animal) in need of it. Subjects for which the benefits ofthe compounds of the invention are intended for administration include,in addition to humans, livestock, domesticated, zoo and companionanimals.

As discussed above this invention provides method for use of compoundsthat have biological properties useful for modulating aldosteronesynthesis. In certain embodiments, the inventive compounds are usefulfor the treatment of chronic renal disease and hypertension. Otherconditions related to elevated aldosterone levels, orhyperaldosteronism, include hypertensive vascular complications(hypertrophy followed by sclerosis of intimal smooth muscle), renalcomplications (sclerosis), and cardiac complications (hypertrophyfollowed by dilatation). Symptoms of elevated aldosterone levelstreatable by the compounds, compositions and methods herein includefatigue, headache, hypokalemia, hypernatraemia, hypomagnesemia,intermittent or temporary paralysis, muscle spasms, muscle weakness,numbness, polyuria, polydipsia, tingling, and metabolic alkalosis, byway of non-limiting examples.

As discussed above this invention provides method for use of compoundsthat have biological properties useful for reducing fibrosis. In certainembodiments, the inventive compounds are useful for the treatment offibrotic liver disease, hepatic ischemia-reperfusion injury, cerebralinfarction, ischemic heart disease, cardiac fibrosis, renal disease orlung (pulmonary) fibrosis. In other embodiments, the disease orcondition is liver fibrosis associated with hepatitis C, hepatitis B,delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis,extrahepatic obstructions (stones in the bile duct), cholangiopathies(primary biliary cirrhosis and sclerosing cholangitis), autoimmune liverdisease, and inherited metabolic disorders (Wilson's disease,hemochromatosis, and alpha-1 antitrypsin deficiency); damaged and/orischemic organs, transplants or grafts; ischemia/reperfusion injury;stroke; cerebrovascular disease; myocardial ischemia; atherosclerosis;pancreatitis; renal failure; renal fibrosis; chronic kidney disease;polycystic kidney disease; scleroderma; systemic sclerosis; dermalfibrosis and idiopathic pulmonary fibrosis. In still furtherembodiments, the treatment is for wounds for acceleration of healing;reducing post-surgical scarring; reducing adhesion formation;vascularization of a damaged and/or ischemic organ, transplant or graft;amelioration of ischemia/reperfusion injury in the brain, heart, liver,kidney, and other tissues and organs; normalization of myocardialperfusion as a consequence of chronic cardiac ischemia or myocardialinfarction; development or augmentation of collateral vessel developmentafter vascular occlusion or to ischemic tissues or organs; fibroticdiseases; hepatic disease including fibrosis and cirrhosis; lungfibrosis; radiocontrast nephropathy; fibrosis secondary to renalobstruction; renal trauma and transplantation; renal failure secondaryto chronic diabetes and/or hypertension; muscular dystrophy, amyotrophiclateral sclerosis, and/or diabetes mellitus.

Thus, as described above, in another aspect of the invention, a methodfor the treatment of disorders related to hyperaldosteronism or elevatedaldosterone levels is provided comprising administering atherapeutically effective amount of a compound of Formula (I) asdescribed herein, to a subject in need thereof. In certain embodimentsof special interest the inventive method is used for the treatment ofchronic renal disease and hypertension. Other diseases of interest aredescribed herein above. It will be appreciated that the compounds andcompositions, according to the method of the present invention, may beadministered using any amount and any route of administration effectivefor the treatment of conditions or diseases in which anti-fibrotics havea therapeutically useful role. Thus, the expression “effective amount”as used herein, refers to a sufficient amount of agent to modulatefibrosis and to exhibit a therapeutic effect. The exact amount requiredwill vary from subject to subject, depending on the species, age, andgeneral condition of the subject, the severity of the infection, theparticular therapeutic agent, its mode and/or route of administration,and the like. The compounds of the invention are preferably formulatedin dosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of therapeutic agent appropriate for the patient to betreated. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present invention will be decidedby the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any particularpatient or organism will depend upon a variety of factors including thedisorder being treated and the severity of the disorder; the activity ofthe specific compound employed; the specific composition employed; theage, body weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts.

Furthermore, after formulation with an appropriate pharmaceuticallyacceptable carrier in a desired dosage, the pharmaceutical compositionsof this invention can be administered to humans and other animalsorally, rectally, parenterally, intracisternally, intravaginally,intraperitoneally, subcutaneously, intradermally, intra-ocularly,topically (as by powders, ointments, or drops), buccally, as an oral ornasal spray, or the like, depending on the severity of the disease ordisorder being treated. In certain embodiments, the compounds of theinvention may be administered at dosage levels of about 0.001 mg/kg toabout 50 mg/kg, preferably from about 0.1 mg/kg to about 10 mg/kg forparenteral administration, or preferably from about 1 mg/kg to about 50mg/kg, more preferably from about 10 mg/kg to about 50 mg/kg for oraladministration, of subject body weight per day, one or more times a day,to obtain the desired therapeutic effect. It will also be appreciatedthat dosages smaller than 0.001 mg/kg or greater than 50 mg/kg (forexample 50-100 mg/kg) can be administered to a subject. In certainembodiments, compounds are administered orally or parenterally.

Compounds of the invention inhibit aldosterone synthase or CYP11B2. Incertain embodiments, compounds of the invention selectively inhibitCYP11B2 compared to CYP11B1. In certain embodiments, compounds of theinvention are at least two times more potent at inhibiting CYP11B2 thanCYP11B1. In certain embodiments, compounds of the invention are at leastfive times more potent at inhibiting CYP11B2 than CYP11B1. In certainembodiments, compounds of the invention are at least ten times morepotent at inhibiting CYP11B2 than CYP11B1. In certain embodiments,compounds of the invention are at least 50 times more potent atinhibiting CYP11B2 than CYP11B1. In certain embodiments, compounds ofthe invention are at least 100 times more potent at inhibiting CYP11B2than CYP11B1. In certain embodiments, compounds of the invention greaterthan 100 times more potent at inhibiting CYP11B2 than CYP11B1.

Moreover, pharmaceutical compositions comprising one or more compoundsof the invention may also contain other compounds or agents for whichco-administration with the compound(s) of the invention istherapeutically advantageous. As many pharmaceutical agents are used inthe treatment of the diseases and disorders for which the compounds ofthe invention are also beneficial, any may be formulated together foradministration. Synergistic formulations are also embraced herein, wherethe combination of at least one compound of the invention and at leastone other compounds act more beneficially than when each is given alone.Non-limiting examples of pharmaceutical agents that may be combinedtherapeutically with compounds of the invention include (non-limitingexamples of diseases or conditions treated with such combination areindicated in parentheses): antivirals and antifibrotics, such asinterferon alpha (hepatitis B, and hepatitis C), combination ofinterferon alpha and ribavirin (hepatitis C), Lamivudine (hepatitis B),Adefovir dipivoxil (hepatitis B), interferon gamma (idiopathic pulmonaryfibrosis, liver fibrosis, and fibrosis in other organs); anticoagulants,e.g., heparin and warfarin (ischemic stroke); antiplatelets e.g.,aspirin, ticlopidine and clopidogrel (ischemic stroke); other growthfactors involved in regeneration, e.g., VEGF and FGF and mimetics ofthese growth factors; antiapoptotic agents; and motility and morphogenicagents.

Treatment Kit

In other embodiments, the present invention relates to a kit forconveniently and effectively carrying out the methods in accordance withthe present invention. In general, the pharmaceutical pack or kitcomprises one or more containers filled with one or more of theingredients of the pharmaceutical compositions of the invention. Suchkits are especially suited for the delivery of solid oral forms such astablets or capsules. Such a kit preferably includes a number of unitdosages, and may also include a card having the dosages oriented in theorder of their intended use. If desired, a memory aid can be provided,for example in the form of numbers, letters, or other markings or with acalendar insert, designating the days in the treatment schedule in whichthe dosages can be administered. Alternatively, placebo dosages, orcalcium dietary supplements, either in a form similar to or distinctfrom the dosages of the pharmaceutical compositions, can be included toprovide a kit in which a dosage is taken every day. Optionallyassociated with such container(s) can be a notice in the form prescribedby a governmental agency regulating the manufacture, use or sale ofpharmaceutical products, which notice reflects approval by the agency ofmanufacture, use or sale for human administration.

EQUIVALENTS

The representative examples that follow are intended to help illustratethe invention, and are not intended to, nor should they be construed to,limit the scope of the invention. Indeed, various modifications of theinvention and many further embodiments thereof, in addition to thoseshown and described herein, will become apparent to those skilled in theart from the full contents of this document, including the exampleswhich follow and the references to the scientific and patent literaturecited herein. It should further be appreciated that the contents ofthose cited references are incorporated herein by reference to helpillustrate the state of the art.

The following examples contain important additional information,exemplification and guidance that can be adapted to the practice of thisinvention in its various embodiments and the equivalents thereof.

EXEMPLIFICATION

The compounds of this invention and their preparation can be understoodfurther by the examples that illustrate some of the processes by whichthese compounds are prepared or used. It will be appreciated, however,that these examples do not limit the invention. Variations of theinvention, now known or further developed, are considered to fall withinthe scope of the present invention as described herein and ashereinafter claimed.

1) General Description of Synthetic Methods:

The practitioner has a well-established literature of small moleculechemistry to draw upon, in combination with the information containedherein, for guidance on synthetic strategies, protecting groups, andother materials and methods useful for the synthesis of the compounds ofthis invention.

The various references cited herein provide helpful backgroundinformation on preparing compounds similar to the inventive compoundsdescribed herein or relevant intermediates, as well as information onformulation, uses, and administration of such compounds which may be ofinterest.

Moreover, the practitioner is directed to the specific guidance andexamples provided in this document relating to various exemplarycompounds and intermediates thereof.

The compounds of this invention and their preparation can be understoodfurther by the examples that illustrate some of the processes by whichthese compounds are prepared or used. It will be appreciated, however,that these examples do not limit the invention. Variations of theinvention, now known or further developed, are considered to fall withinthe scope of the present invention as described herein and ashereinafter claimed.

According to the present invention, any available techniques can be usedto make or prepare the inventive compounds or compositions includingthem. For example, a variety of solution phase synthetic methods such asthose discussed in detail below may be used. Alternatively oradditionally, the inventive compounds may be prepared using any of avariety combinatorial techniques, parallel synthesis and/or solid phasesynthetic methods known in the art.

It will be appreciated as described below, that a variety of inventivecompounds can be synthesized according to the methods described herein.The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCompany (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis,Mo.), or are prepared by methods well known to a person of ordinaryskill in the art following procedures described in such references asFieser and Fieser 1991, “Reagents for Organic Synthesis”, vols 1-17,John Wiley and Sons, New York, N.Y., 1991; Rodd 1989 “Chemistry ofCarbon Compounds”, vols. 1-5 and supps, Elsevier Science Publishers,1989; “Organic Reactions”, vols 1-40, John Wiley and Sons, New York,N.Y., 1991; March 2001, “Advanced Organic Chemistry”, 5th ed. John Wileyand Sons, New York, N.Y.; and Larock 1990, “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations”, 2^(nd) ed.VCH Publishers. These schemes are merely illustrative of some methods bywhich the compounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to aperson of ordinary skill in the art having regard to this disclosure.

The starting materials, intermediates, and compounds of this inventionmay be isolated and purified using conventional techniques, includingfiltration, distillation, crystallization, chromatography, and the like.They may be characterized using conventional methods, including physicalconstants and spectral data.

General Reaction Procedures:

Unless mentioned specifically, reaction mixtures are stirred using amagnetically driven stirrer bar. An inert atmosphere refers to eitherdry argon or dry nitrogen. Reactions are monitored either by thin layerchromatography, by proton nuclear magnetic resonance (NMR) or byhigh-pressure liquid chromatography (HPLC), of a suitably worked upsample of the reaction mixture.

General Work Up Procedures:

Unless mentioned specifically, reaction mixtures are cooled to roomtemperature or below then quenched, when necessary, with either water ora saturated aqueous solution of ammonium chloride. Desired products areextracted by partitioning between water and a suitable water-immisciblesolvent (e.g. ethyl acetate, dichloromethane, diethyl ether). Thedesired product containing extracts are washed appropriately with waterfollowed by a saturated solution of brine. On occasions where theproduct containing extract is deemed to contain residual oxidants, theextract is washed with a 10% solution of sodium sulphite in saturatedaqueous sodium bicarbonate solution, prior to the aforementioned washingprocedure. On occasions where the product containing extract is deemedto contain residual acids, the extract is washed with saturated aqueoussodium bicarbonate solution, prior to the aforementioned washingprocedure (except in those cases where the desired product itself hadacidic character). On occasions where the product containing extract isdeemed to contain residual bases, the extract is washed with 10% aqueouscitric acid solution, prior to the aforementioned washing procedure(except in those cases where the desired product itself had basiccharacter). Post washing, the desired product containing extracts aredried over anhydrous magnesium sulphate, and then filtered. The crudeproducts are then isolated by removal of solvent(s) by rotaryevaporation under reduced pressure, at an appropriate temperature(generally less than 45° C.).

General Purification Procedures:

Unless mentioned specifically, chromatographic purification refers toflash column chromatography on silica, using a single solvent or mixedsolvent as eluent. Suitably purified desired product containing elutesare combined and concentrated under reduced pressure at an appropriatetemperature (generally less than 45° C.) to constant mass.

Example 1:1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)-2-methylpropan-1-ol

Step-1: To a solution of 4-ethoxynicotinaldehyde (234 mg, 1.55 mmol) inTHF (10 mL) at −30° C. was added isopropylmagnesium bromide (1M in THF,1.6 mL, 1.6 mmol) and the mixture was allowed to warm to RT and stirredfor 1 h. Water was added, and the mixture was evaporated under reducedpressure. To the residue was added water and extracted withdichloromethane. The organic layer was washed with brine, dried overanhydrous sodium sulfate and evaporated under reduced pressure. Thecrude product was purified by silica gel chromatography (ISCO CombiFlashCompanion) using 0→5% methanol in DCM as eluent to afford1-(4-ethoxypyridin-3-yl)-2-methylpropan-1-ol. 1H NMR (CDCl3, 300 MHz): δ0.78 (d, J=6.9 Hz, 3H), 0.96 (d, J=6.9 Hz, 3H), 1.40 (t, J=7.2 Hz, 3H),1.92-2.1 (m, 1H), 3.41 (bs, 1H), 4.05 (dq, J=6.9, 1.8 Hz, 2H), 4.55 (d,J=6.9 Hz, 1H), 6.68 (d, J=6.0 Hz, 1H), 8.27 (d, J=6.0 Hz, 1H), 8.34 (s,1H).

Step-2: To a solution of oxalyl chloride (2M in DCM, 0.375 mL, 0.75mmol) in dichloromethane (4 mL) at −78° C. was added drop wise dimethylsulfoxide (0.106 mL, 1.5 mmol), and the mixture was stirred for 30 min.1-(4-Ethoxypyridin-3-yl)-2-methylpropan-1-ol (98 mg, 0.5 mmol) indichloromethane (2 mL) was added to the reaction mixture at −78° C. andstirring was continued for 1 h. Triethylamine (0.313 mL, 2.25 mmol) wasadded and the reaction was allowed to warm to RT. Water was added to thereaction mixture and was extracted with dichloromethane. The organiclayer was washed with brine, dried over anhydrous sodium sulfate andevaporated under reduced pressure. The crude product was purified bysilica gel chromatography (ISCO CombiFlash Companion) using 0→25% ethylacetate in hexanes as eluent to afford1-(4-ethoxypyridin-3-yl)-2-methylpropan-1-one. 1H NMR (CDCl3, 300 MHz):δ 1.16 (d, J=6.9 Hz, 6H), 1.49 (t, J=7.2 Hz, 3H), 3.38-3.51 (m, 1H),4.18 (q, J=6.9 Hz, 2H), 6.83 (d, J=6.0 Hz, 1H), 8.51 (d, J=6.0 Hz, 1H),8.63 (s, 1H).

Step-3: To a solution of 7-bromobenzo[d]thiazole (24.4 mg, 0.114 mmol)in THF (3 mL) at −78° C. was added LDA (2M in THF/hexanes, 0.068 mL,0.137 mmol) and the mixture was stirred for 10 min. To the reactionmixture was added 1-(4-ethoxypyridin-3-yl)-2-methylpropan-1-one (22 mg,0.114 mmol) in THF (2 mL) and the mixture was stirred at −78° C. for 30min. The reaction was quenched with water, evaporated under reducedpressure. To the residue was added water and DCM and extracted. The DCMlayer was washed with brine, dried over anhydrous sodium sulfate andevaporated under reduced pressure. Purification of the crude product bysilica gel chromatography (ISCO CombiFlash Companion) using 0-5%methanol in dichloromethane as eluent afforded1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)-2-methylpropan-1-ol.1H NMR (CDCl3, 300 MHz): δ 0.94 (d, J=6.9 Hz, 3H), 1.02 (d, J=6.9 Hz,3H), 1.52 (t, J=7.2 Hz, 3H), 3.05-3.15 (m, 1H), 4.10-4.28 (m, 2H), 5.63(s, 1H), 6.78 (d, J=3.9 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.48 (dd,J=7.8, 0.3 Hz, 1H), 7.89 (dd, J=6.9, 0.9 Hz, 1H), 8.41 (d, J=5.7, 1H),8.91 (s, 1H). MS (ES+): m/z 407.1 (M+).

Using the above procedure the following compounds have been prepared:

Example 2: 1-(6-bromobenzo[d]thiazol-2-yl)-1-(pyridin-3-yl)butan-1-ol.MS (ES+): m/z 362.01 (MH+) Example 3:1-(6-bromobenzo[d]thiazol-2-yl)-2,2-dimethyl-1-(pyridin-3-yl)propan-1-ol.MS (ES−): m/z 377.02 (M−1) Example 4:(6-bromobenzo[d]thiazol-2-yl)(cyclopropyl)(pyridin-3-yl)methanol. MS(ES−): m/z 361.2 (M−1) Example 5:1-(6-bromobenzo[d]thiazol-2-yl)-3-methyl-1-(pyridin-3-yl)butan-1-ol. MS(ES): m/z 377.2 (M−1) Example 6:1-(benzo[d]thiazol-2-yl)-1-(pyridin-3-yl)butan-1-ol. MS (ES−): m/z 385.1(M−1) Example 7:1-(5-bromobenzo[d]thiazol-2-yl)-2-methyl-1-(pyridin-3-yl)propan-1-ol. MS(ES+): m/z 363.27 (MH+) Example 8:1-(7-bromobenzo[d]thiazol-2-yl)-2-methyl-1-(pyridin-3-yl)propan-1-ol. MS(ES+): m/z 363.2 (MH+) Example 9:1-(6-bromobenzo[d]thiazol-2-yl)-2-methyl-1-(pyridin-3-yl)propan-1-ol. MS(ES+): m/z 362.01 (MH+) Example 10:1-(6-bromobenzo[d]thiazol-2-yl)-1-(pyridin-3-yl)propan-1-ol. MS (ES+):m/z 349.2 (MH+) Example 11:1-(6-bromobenzo[d]thiazol-2-yl)-2-methyl-1-(pyridin-3-yl)propan-1-ol. MS(ES+): m/z 363.2 (MH+) Example 12:1-(6-bromobenzo[d]thiazol-2-yl)-1-(pyridin-3-yl)ethanol. MS (ES+): m/z335.2 (MH+) Example 13:1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol. MS(ES+): m/z 393.2 (MH+) Example 14:1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-chloropyridin-3-yl)butan-1-ol. MS(ES+): m/z 397.2 (MH+) Example 15:1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-bromopyridin-3-yl)butan-1-ol. MS(ES+): m/z 443.2 (MH+) Example 16:1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-phenylpyridin-3-yl)butan-1-ol. MS(ES+): m/z 439.2 (MH+) Example 17:1-(5-bromobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol. MS(ES+): m/z 393.2 (MH+) Example 18:1-(5-(diisopropylamino)benzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol.MS (ES+): m/z 414.2 (MH+) Example 19:1-(7-bromobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol. MS(ES+): m/z 393.2 (MH+) Example 20:1-(6-fluorobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol. MS(ES+): m/z 333.2 (MH+) Example 21:1-([3,3′-bipyridin]-5-yl)-1-(6-bromobenzo[d]thiazol-2-yl)butan-1-ol. MS(ES+): m/z 440.2 (MH+) Example 22:1-(7-bromobenzo[d]thiazol-2-yl)-1-(pyridin-3-yl)butan-1-ol. MS (ES+):m/z 363.2 (MH+) Example 23:1-(6-bromobenzo[d]thiazol-2-yl)-1-(6-methoxypyridin-3-yl)butan-1-ol. MS(ES+): m/z 393.1 (MH+) Example 24:1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)butan-1-ol. MS(ES+): m/z 393 (MH+) Example 25:1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2-methylpropan-1-ol.MS (ES+): m/z 393 (MH+) Example 26:(6-bromobenzo[d]thiazol-2-yl)(4-methoxypyridin-3-yl)methanol. MS (ES+):m/z 351 (MH+) Example 27:(7-bromobenzo[d]thiazol-2-yl)(4-methoxypyridin-3-yl)methanol. MS (ES+):m/z 351 (MH+) Example 28:1-(4-methoxypyridin-3-yl)-1-(6-nitrobenzo[d]thiazol-2-yl)butan-1-ol. MS(ES+): m/z 360.1 (MH+) Example 29:1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol. MS(ES+): m/z 407.1 (MH+) Example 30:1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol. MS(ES+): m/z 407.1 (MH+) Example 31:1-(benzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2,2-dimethylpropan-1-ol.MS (ES+): m/z 329.1 (MH+) Example 32:1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)-2-methylpropan-1-ol.MS (ES+): m/z 407.1 (MH+) Example 33:1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)-2-methylpropan-1-ol.MS (ES+): m/z 405.1 (MH+) Example 34:1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)-2-methylpropan-1-ol.MS (ES+): m/z 405.1 (MH+) Example 35:1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-isopropoxypyridin-3-yl)-2-methylpropan-1-ol.MS (ES+): m/z 421.1 (MH+) Example 36:1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-isopropoxypyridin-3-yl)-2-methylpropan-1-ol.MS (ES+): m/z 421.1 (MH+) Example 37:1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)butan-1-ol.MS (ES+): m/z 405.1 (MH+) Example 38:1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)butan-1-ol.MS (ES+): m/z 405.1 (MH+) Example 39:1-(6-chlorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol. MS(ES+): m/z 363.1 (MH+) Example 40:1-(4-ethoxypyridin-3-yl)-1-(6-nitrobenzo[d]thiazol-2-yl)butan-1-ol. MS(ES+): m/z 374.1 (MH+) Example 41:1-(4-ethoxypyridin-3-yl)-1-(6-fluorobenzo[d]thiazol-2-yl)butan-1-ol. MS(ES+): m/z 347.1 (MH+) Example 42:1-(7-chlorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol. MS(ES+): m/z 363.1 (MH+) Example 43:1-(4,7-difluorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol.MS (ES+): m/z 365.16 (MH+) Example 44:1-(4-ethoxypyridin-3-yl)-1-(7-methoxybenzo[d]thiazol-2-yl)butan-1-ol. MS(ES+): m/z 359.2 (MH+) Example 45:1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol.MS (ES+): m/z 397.1 (MH+) Example 46:1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol.MS (ES+): m/z 413.1 (MH+) Example 47:1-(4-ethoxypyridin-3-yl)-1-(7-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol.MS (ES+): m/z 397.1 (MH+) Example 48:1-(4-ethoxypyridin-3-yl)-1-(6-methoxybenzo[d]thiazol-2-yl)butan-1-ol. MS(ES+): m/z 359.2 (MH+) Example 49:1-(4-isopropoxypyridin-3-yl)-1-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol.MS (ES+): m/z 427.1 (MH+) Example 50:1-(5,6-dichlorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol.MS (ES+): m/z 397.1 Example 51:1-(4-propoxypyridin-3-yl)-1-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol.MS (ES+): m/z 427.1 (MH+) Example 52:1-(2,2-difluoro-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]thiazol-6-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol.MS (ES+): m/z 409.1 (MH+) Example 53:1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2-methylpropan-1-ol.MS (ES+): m/z 393.1 (MH+) Example 54:1-(4-ethoxypyridin-3-yl)-1-(6-(4-(trifluoromethoxy)phenoxy)benzo[d]thiazol-2-yl)butan-1-ol.MS (ES+): m/z 505.14 (MH+) Example 55:1-(4-ethoxypyridin-3-yl)-1-(6-(4-fluorophenoxy)benzo[d]thiazol-2-yl)butan-1-ol.MS (ES+): m/z 439.12 (MH+) Example 56:1-(5-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol.MS (ES+): m/z 493.03 (MH+) Example 57:1-(7-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol.MS (ES+): m/z 491.00 (M+) Example 58:1-(5-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol.MS (ES+): m/z 447.05 (MH+) Example 59:1-(7-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol.MS (ES+): m/z 447.20 (MH+) Example 60:1-(4-ethoxypyridin-3-yl)-1-(5-methyl-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol.MS (ES+): m/z 427.10 (MH+) Example 61:1-(4-ethoxypyridin-3-yl)-1-(7-methyl-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol.MS (ES+): m/z 427.10 (MH+) Example 62:1-(4-ethoxypyridin-3-yl)-1-(5-fluoro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol.MS (ES+): m/z 431.15 (MH+) Example 63:1-(5-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol.MS (ES+): m/z 461.13 (MH+) Example 64:1-(7-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol.MS (ES+): m/z 461.13 (MH+) Example 65:1-(6-bromo-5,7-dichlorobenzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol.MS (ES+): m/z 476.94 (M+) Example 66:1-(4-propoxypyridin-3-yl)-1-(5,6,7-trichlorobenzo[d]thiazol-2-yl)butan-1-ol.MS (ES+): m/z 430.99 (M+) Example 67:1-(5,7-dichloro-6-(2,2,2-trifluoroethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol.MS (ES+): m/z 495.04 (M+) Example 68:1-(7-chloro-6-(2,2,2-trifluoroethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol.MS (ES+): m/z 461.07 (MH+) Example 69:1-(5-chloro-6-(2,2,2-trifluoroethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol.MS (ES+): m/z 461.3 (MH+) Example 70:1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)butan-1-ol. MS(ES+): m/z 393.2 (M+) Example 71:1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2-methylpropan-1-olMS (ES+): m/z 393.1 (M+) Example 72:1-(6-cyanobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol. MS(ES+): m/z 354.2 (MH+) Example 73:2-(1-(4-ethoxypyridin-3-yl)-1-hydroxybutyl)benzo[d]thiazole-6-carboxamide.MS (ES+): m/z 372.2 (MH+)

Using the above procedure, the following compounds can also be prepared:(R)-1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethoxy)-7-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;(R)-1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;(S)-1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethoxy)-7-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;(S)-1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethoxy)-5-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(7-methoxy-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-propoxypyridin-3-yl)-1-(6-(trifluoromethoxy)-5-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-propoxypyridin-3-yl)-1-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-1ol;1-(5,6-bis(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(5-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(6,7-bis(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxy-5-methoxypyridin-3-yl)butan-1-ol;1-(7-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxy-5-methoxypyridin-3-yl)butan-1-ol;1-(7-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxy-5-methoxypyridin-3-yl)butan-1-ol;1-(5,7-difluoro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(5,7-dichloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-oland 1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol.

Example 74: Assessment of Aldosterone Inhibitory Activity

For the determination of aldosterone inhibitory activity, tests werecarried out using V79 Chinese hamster cells stably transfected withhuman CYP11B2 or CYP11B1 and using assay protocols as described in EhmerP B, Bureik M, Bernhardt R, Muller U, Hartmann R W. Development of atest system for inhibitors of human aldosterone synthase (CYP11B2):screening in fission yeast and evaluation of selectivity in V79 cells.J. Steroid Biochem. Mol. Biol. 2002 June; 81(2):173-9. The concentrationof the substrate 11-deoxycorticosterone in the assay was 100 nM. FIG. 1shows for one exemplary compound that the inhibition of the product ofgene CYP11B2, aldosterone synthase, is high whereas the inhibition ofthe related enzyme CYP11B1 is significantly less, by a factor of about70 fold.

The following compounds of Formula (I) inhibited the production ofaldosterone with an IC50 of <1 μM in V79 Chinese hamster cells.1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)-2-methylpropan-1-ol;1-(6-fluorobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2-methylpropan-1-ol;(6-bromobenzo[d]thiazol-2-yl)(4-methoxypyridin-3-yl)methanol;(7-bromobenzo[d]thiazol-2-yl)(4-methoxypyridin-3-yl)methanol;1-(4-methoxypyridin-3-yl)-1-(6-nitrobenzo[d]thiazol-2-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(benzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2,2-dimethylpropan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)-2-methylpropan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)-2-methylpropan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)-2-methylpropan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-isopropoxypyridin-3-yl)-2-methylpropan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-isopropoxypyridin-3-yl)-2-methylpropan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)butan-1-ol;1-(6-chlorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-nitrobenzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-fluorobenzo[d]thiazol-2-yl)butan-1-ol;1-(7-chlorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4,7-difluorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(7-methoxybenzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(7-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-methoxybenzo[d]thiazol-2-yl)butan-1-ol;1-(4-isopropoxypyridin-3-yl)-1-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(5,6-dichlorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4-propoxypyridin-3-yl)-1-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(2,2-difluoro-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]thiazol-6-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2-methylpropan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(4-(trifluoromethoxy)phenoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(4-fluorophenoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(5-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(7-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(5-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(7-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(5-methyl-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(7-methyl-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(5-fluoro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(5-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(7-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(6-bromo-5,7-dichlorobenzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(4-propoxypyridin-3-yl)-1-(5,6,7-trichlorobenzo[d]thiazol-2-yl)butan-1-ol;1-(5,7-dichloro-6-(2,2,2-trifluoroethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(7-chloro-6-(2,2,2-trifluoroethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(5-chloro-6-(2,2,2-trifluoroethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2-methylpropan-1-ol;1-(6-cyanobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;2-(1-(4-ethoxypyridin-3-yl)-1-hydroxybutyl)benzo[d]thiazole-6-carboxamide.

Example 75: Assessment of Aldosterone Synthase Inhibitory Activity

To test the activity of compounds in a cell-based assay, awell-established assay described in the literature was used[Muller-Vieira U, Angotti M, Hartmann R W. The adrenocortical tumor cellline NCI-H295R as an in vitro screening system for the evaluation ofCYP11B2 (aldosterone synthase) and CYP11B1 (steroid-11beta-hydroxylase)inhibitors. J Steroid Biochem Mol Biol 2005 August; 96(3-4):259-70;Ulleras E, Ohlsson A, Oskarsson A. Secretion of cortisol and aldosteroneas a vulnerable target for adrenal endocrine disruption-screening of 30selected chemicals in the human H295R cell model. J Appl Toxicol 2008November; 28(8):1045-53; Jager L P, De Graaf G J, Widjaja-Greefkes H C.Screening for drug-induced alterations in the production and release ofsteroid hormones by porcine adrenocortical cells in vitro. Toxicol InVitro 1996 October; 10(5):595-608.]. In brief, human adrenocorticalcarcinoma cells (H295R; ATCC CRL-2128) were plated in 96-well plates andthe effect of compounds on angiotensin-II (Ang-II) stimulatedaldosterone production was determined in the supernatant using an ELISAkit (Genway 40-521-475012). Positive control compounds such as etomidateand the promiscuous P450 inhibitor ketoconazole significantly inhibitedboth the basal and the Ang-II stimulated aldosterone production in thisassay. Compounds were tested in the aldosterone production assay atvarious concentrations and from dose-response inhibition curves the %inhibition at specific concentrations and the IC50 were calculated.

The following compounds of Formula (I) inhibited the production ofaldosterone with an IC₅₀ of 1 μM-10 μM in NCI-H295R cells.1-(6-bromobenzo[d]thiazol-2-yl)-1-(pyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-2,2-dimethyl-1-(pyridin-3-yl)propan-1-ol;(6-bromobenzo[d]thiazol-2-yl)(cyclopropyl)(pyridin-3-yl)methanol;1-(6-bromobenzo[d]thiazol-2-yl)-3-methyl-1-(pyridin-3-yl)butan-1-ol;1-(benzo[d]thiazol-2-yl)-1-(pyridin-3-yl)butan-1-ol;1-(5-bromobenzo[d]thiazol-2-yl)-2-methyl-1-(pyridin-3-yl)propan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-2-methyl-1-(pyridin-3-yl)propan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-2-methyl-1-(pyridin-3-yl)propan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(pyridin-3-yl)propan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(pyridin-3-yl)ethanol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-chloropyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-bromopyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-phenylpyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol;1-([3,3′-bipyridin]-5-yl)-1-(6-bromobenzo[d]thiazol-2-yl)butan-1-ol; and1-(7-bromobenzo[d]thiazol-2-yl)-1-(pyridin-3-yl)butan-1-ol.

Example 76: Test Compound Ameliorates Renal Fibrosis in the Mouse UUOModel

An exemplary compound was tested in the mouse unilateral urethralobstruction (UUO) model. Adult male mice were subjected to UUO vialigation of the left renal artery, while keeping the contralateral rightkidney intact. In this model, marked induction of fibrosis is observedas early as four days after UUO and this is seen to progress in animalssacrificed ten days after UUO.

Starting the day of UUO, animals were treated orally with 25 mg/kg ofcompound twice every day for 10 days. Test compound reduced the increasein kidney weight (FIG. 2A) and kidney collagen deposition(hydroxyproline and Sirius Red Staining, FIGS. 2B and 2C, respectively)observed in the vehicle treated group. Test compound also affected alphasmooth muscle actin staining (FIG. 2D), which is another, earlybiomarker for the development of fibrosis. Overall, these observationsindicate that aldosterone synthase inhibition has an anti-fibroticactivity in the mouse UUO model. Since the UUO does not result inincreased blood pressure, the anti-fibrotic activity of the testcompound is not likely to be due to blood pressure lowering activity.

Example 77: Test Compound Improves Renal Function in the Rat RemnantKidney Model of CKD

The effect of test compound was also tested in the rat remnant kidneymodel. Animals were subjected to 5/6 nephrectomy and placed in metaboliccages to collect urine samples for determination of albuminuria. Markedincreases were found in urine albumin levels, as well as elevated serumBUN and creatinine concentration. The rats with overt renal dysfunctionwere then randomized to vehicle and test compound (25 mg/kg, po, bid)treatment groups. After one month of compound or vehicle treatment, andprior to sacrifice, urine was collected for urine analysis, and bloodpressure was measured to determine the effects of test compound on bloodpressure. While 5/6 nephrectomy—as expected—markedly elevated the bloodpressure, this elevated BP was reduced to normal by test compoundtreatment (FIG. 3). Test compound markedly reduced serum BUN andcreatinine levels (FIG. 4A; left bar, BUN; right bar, creatinine),kidney collagen content (as determined by hydroxyproline assay; FIG. 4B)and improved renal histology (FIG. 5), both in the structural integrityof glomeruli as of proximal and distal convoluted tubules. Importantly,renal function, as determined by urine albumin to creatinine ratio (FIG.4C) and by the concentration of neutrophil gelatinase-associatedlipocalin (NGAL; a sensitive urine biomarker of tubule-interstitialinjury) in the urine (FIG. 4D), showed marked improvements. Takentogether, this study indicated marked improvement in renal function bycompound treatment compared to animals receiving vehicle treatment.

Example 78: Test Compound Improves Renal Function in the Rat PolycysticKidney Disease Model

A compound of the invention was tested in the PCK rat, a model ofautosomal recessive polycystic kidney disease (ARPKD). PCK rats (CharlesRiver) carry and autosomal recessive Pkhd1 gene mutation, which resultsin genetically determined cytogenesis and fibrosis in both kidney andlivers. Already at the age of 6 weeks, PCK rats have markedly enlargedkidneys and livers as a result of this cyst formation. PCK animals orSprague Dawley control animals were dosed with test compound twice a dayat 25 mg/kg from the age of 6 weeks to the age of 10 weeks. From week 6to 10, there is a significant increase in kidney size and the % area ofcysts, as determined by quantitative histochemistry of H&E slides. Testcompound reduced this increase in kidney weight and the % cystic areafrom week 6 to week 10 (FIG. 6A) and as expressed as percent ofpre-treatment kidney weight, FIG. 6B). While the kidney weight and %cystic area in PCK rats increased from week 6 to 10 in vehicle treatedanimals by approximately 20% and 60% respectively, kidney weight andkidney cystic area were not significantly increased in animals treatedwith test compound (FIG. 7A; as percent of pre-treatment cystic area,FIG. 7B). This indicates that the disease progression has beensignificantly slowed down, a key objective for prospective therapeuticsfor polycystic kidney disease. Kidney collagen deposition (Sirius Redstaining; FIG. 8) and proteinuria (determined in the urine just prior tosacrifice of animals for tissue harvest; FIG. 9) were also ameliorated,indicating that progression to a fibrotic state and deterioration ofkidney function are also halted by compound administration. In addition,test compound significantly improves the liver pathology associated withrenal dysfunction, as observed e.g. in the increase in liver collagendeposition (hydroxyproline) and Sirius Red staining (FIG. 10). Overall,these observations indicate that aldosterone synthase inhibition has abeneficial effect on both kidney and liver manifestations of diseaseprogression in this model of PKD.

What is claimed is:
 1. A compound as described in Formula (I)

or a salt or enantiomer, thereof; wherein R¹ is one, two, or threeindependent halogen, haloalkyl, NO₂, CN, COOR⁵, SO₂R⁵, CONR⁵R⁶,SO₂NR⁵R⁶, NR⁵R⁶, OR⁵, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkylor aryl; R² is one or more independent halogen, haloalkyl, NO₂, CN,COOR⁵, SO₂R⁵, CONR⁵R⁶, SO₂NR⁵R⁶, NR⁵R⁶, OR⁵, alkyl, alkenyl, alkynyl,cycloalkyl, heteroalkyl, or aryl; R³ is alkyl, alkenyl or alkynyl, anyof which is further substituted by one or more R⁷; R⁴ is NR⁵R⁶, SR⁵, orOR⁵; R⁵ and R⁶ are independently hydrogen, alkyl, aryl or haloalkyl; R⁷is H, halogen, alkyl, haloalkyl, NO₂, CN, COOR⁸, SO₂R⁸, CONR⁸R⁹,SO₂NR⁸R⁹, NR⁸R⁹, or OR⁸; and R⁸ and R⁹ are independently hydrogen, alkylor haloalkyl, and wherein the compound is notbenzo[d]thiazol-2-yl(pyridin-3-yl)methanol.
 2. The compound of claim 1wherein each R¹ is independently fluoro, chloro, bromo, phenyl,isopropyl, methoxy, ethyloxy, 1-propyloxy or 2-propyloxy.
 3. Thecompound of claim 1 wherein each R² is independently fluoro, chloro,bromo, cyano, CONH₂, nitro, methyl, ethyl, vinyl, trifluoromethyl,diisopropylamino, trifluoromethoxy, trifluoroethoxy, methoxy, phenoxy,(4-fluoro)phenoxy or (4-trifluoromethoxy)phenoxy.
 4. The compound ofclaim 1 wherein R² represents di-substitution with two same substituentsselected from among difluoro, dichloro, dibromo, dimethyl, dimethoxy,ditrifluoromethyl, ditrifluoroethoxy and ditrifluoromethoxy.
 5. Thecompound of claim 1 wherein R² represents di-substitution with twodifferent substituents selected from fluoro and chloro, fluoro andbromo, fluoro and methoxy, chloro and methoxy, bromo and methoxy, methyland methoxy, trifluoromethyl and methoxy, trifluoromethoxy and methoxy,fluoro and trifluoromethyl, chloro and trifluoromethyl, bromo andtrifluoromethyl, methyl and trifluoromethyl, trifluoromethoxy andtrifluoromethyl, fluoro and trifluoromethoxy, chloro andtrifluoromethoxy, bromo and trifluoromethoxy, methyl andtrifluoromethoxy, trifluoromethyl and trifluoromethoxy, fluoro andtrifluoroethoxy, chloro and trifluoroethoxy, bromo and trifluoroethoxy,methyl and trifluoroethoxy, trifluoromethoxy and trifluoroethoxy, andtrifluoromethyl and trifluoroethoxy.
 6. The compound of claim 1 whereinR² represents tri-substitution with three same substituents selectedfrom trifluoro, trichloro and tribromo.
 7. The compound of claim 1wherein R² represents tri-substitution with different substituentsselected from difluoro and chloro, difluoro and bromo, difluoro andtrifluoromethyl, difluoro and trifluoromethoxy, difluoro andtrifluoroethoxy, dichloro and fluoro, dichloro and bromo, dichloro andtrifluoromethyl, dichloro and trifluoromethoxy, dichloro andtrifluoroethoxy, dibromo and fluoro, dibromo and chloro, dibromo andtrifluoromethyl, dibromo and trifluoromethoxy, dibromo andtrifluoroethoxy, chloro, bromo and trifluoromethyl, and chloro, bromoand trifluoromethoxy.
 8. The compound of claim 1 wherein R³ is methyl,ethyl, 1-propyl, 2-propyl, cyclopropyl, isobutyl or t-butyl.
 9. Thecompound of claim 1 wherein R⁴ is SH, NH₂ or OH.
 10. The compound ofclaim 1 selected from1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)-2-methylpropan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-chloropyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-bromopyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(5-phenylpyridin-3-yl)butan-1-ol;1-(5-bromobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol;1-(5-(diisopropylamino)benzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol;1-(6-fluorobenzo[d]thiazol-2-yl)-1-(5-methoxypyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(6-methoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2-methylpropan-1-ol;1-(4-methoxypyridin-3-yl)-1-(6-nitrobenzo[d]thiazol-2-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)-2-methylpropan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)-2-methylpropan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)-2-methylpropan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-isopropoxypyridin-3-yl)-2-methylpropan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-isopropoxypyridin-3-yl)-2-methylpropan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-isopropylpyridin-3-yl)butan-1-ol;1-(6-chlorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-nitrobenzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-fluorobenzo[d]thiazol-2-yl)butan-1-ol;1-(7-chlorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4,7-difluorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(7-methoxybenzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(7-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-methoxybenzo[d]thiazol-2-yl)butan-1-ol;1-(4-isopropoxypyridin-3-yl)-1-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(5,6-dichlorobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4-propoxypyridin-3-yl)-1-(6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2-methylpropan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(4-(methoxy)phenoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(4-fluorophenoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(5-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(7-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(5-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(7-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(5-methyl-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(7-methyl-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;(R)-1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethoxy)-7-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;(R)-1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;(S)-1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethoxy)-7-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;(S)-1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(6-(trifluoromethoxy)-5-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(7-methoxy-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-propoxypyridin-3-yl)-1-(6-(trifluoromethoxy)-5-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;1-(4-propoxypyridin-3-yl)-1-(6-(trifluoromethyl)benzo[d]thiazol-2-yl)butan-1-ol;1-(5,6-bis(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(5-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(6,7-bis(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxy-5-methoxypyridin-3-yl)butan-1-ol;1-(7-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxy-5-methoxypyridin-3-yl)butan-1-ol;1-(7-bromo-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-ethoxy-5-methoxypyridin-3-yl)butan-1-ol;1-(4-ethoxypyridin-3-yl)-1-(5-fluoro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)butan-1-ol;1-(5-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(7-chloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(6-bromo-5,7-dichlorobenzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(4-propoxypyridin-3-yl)-1-(5,6,7-trichlorobenzo[d]thiazol-2-yl)butan-1-ol;1-(5,7-dichloro-6-(2,2,2-trifluoroethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(7-chloro-6-(2,2,2-trifluoroethoxy)benzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol;1-(5-chloro-6-(2,2,2-trifluoroethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(5,7-difluoro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(5,7-dichloro-6-(trifluoromethoxy)benzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;1-(6-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)butan-1-ol;1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-methoxypyridin-3-yl)-2-methylpropan-1-ol;1-(6-cyanobenzo[d]thiazol-2-yl)-1-(4-ethoxypyridin-3-yl)butan-1-ol;2-(1-(4-ethoxypyridin-3-yl)-1-hydroxybutyl)benzo[d]thiazole-6-carboxamide;and 1-(7-bromobenzo[d]thiazol-2-yl)-1-(4-propoxypyridin-3-yl)butan-1-ol.11. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier, diluent or excipient.